WO2015086526A1 - Dérivés d'imidazole tricyclique condensé comme modulateurs de l'activité du tnf - Google Patents

Dérivés d'imidazole tricyclique condensé comme modulateurs de l'activité du tnf Download PDF

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WO2015086526A1
WO2015086526A1 PCT/EP2014/076884 EP2014076884W WO2015086526A1 WO 2015086526 A1 WO2015086526 A1 WO 2015086526A1 EP 2014076884 W EP2014076884 W EP 2014076884W WO 2015086526 A1 WO2015086526 A1 WO 2015086526A1
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alkyl
heteroaryl
optionally substituted
hydroxy
methyl
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PCT/EP2014/076884
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English (en)
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Rikki Peter Alexander
Gareth Neil BRACE
Julien Alistair Brown
Mark Daniel CALMIANO
Praful Tulshi CHOVATIA
Michael Deligny
Ellen Olivia GALLIMORE
Jag Paul Heer
Victoria Elizabeth JACKSON
Boris KROEPLIEN
Malcolm Mac Coss
Joanna Rachel Quincey
Yogesh Anil Sabnis
Dominique Louis Léon SWINNEN
Zhaoning Zhu
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Ucb Biopharma Sprl
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Priority to BR112016012990A priority Critical patent/BR112016012990A2/pt
Priority to CA2931758A priority patent/CA2931758C/fr
Priority to JP2016537474A priority patent/JP6445560B2/ja
Priority to CN201480067053.3A priority patent/CN105814049B/zh
Priority to ES14808658T priority patent/ES2755335T3/es
Priority to RU2016126974A priority patent/RU2679914C9/ru
Priority to US15/101,767 priority patent/US10087179B2/en
Priority to EP14808658.0A priority patent/EP3080113B1/fr
Publication of WO2015086526A1 publication Critical patent/WO2015086526A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a class of fused tricyclic imidazole derivatives, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted fused imidazopyridine derivatives. In particular the present invention relates to dihydro-lH-cyclopenta[4,5]imidazo[l,2-a]pyridine derivatives.
  • These compounds are modulators of the signalling of TNFa, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
  • TNFa is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death.
  • TNF Tumour Necrosis Factor
  • One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors.
  • TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.
  • TNFa inhibitors include anti-TNFa antibodies; and soluble TNFa receptor fusion proteins.
  • anti-TNFa antibodies examples include fully human antibodies such as adalimumab (Humira®) and golimumab (Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab' fragments such as certolizumab pegol (Cimzia®).
  • An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®).
  • TNF superfamily members including TNFa itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M.G. Tansey & D.E. - -
  • the compounds in accordance with the present invention being potent modulators of human TNFa activity, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • certain compounds of this invention may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilised in assays (e.g. a fluorescence polarisation assay) for detecting pharmaco lo gically active compounds .
  • the compounds in accordance with the present invention potently inhibit the binding of a fluorescence conjugate to TNFa when tested in the fluorescence polarisation assay described herein.
  • the compounds of the present invention exhibit an IC 50 value of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • Certain compounds in accordance with the present invention potently neutralise the activity of TNFa in a commercially available HEK-293 derived reporter cell line known as HEK-BlueTM CD40L.
  • HEK-BlueTM CD40L This is a stable HEK-293 transfected cell line expressing SEAP (secreted embryonic alkaline phosphatase) under the control of the IFNP minimal - -
  • certain compounds of the present invention exhibit an IC 50 value of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (as before, the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • the present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
  • Y represents C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • Z represents a heteroatom, carbonyl; -S(O)-, -S(0) 2 -, -S(0)(N-R d ), -NC(0)R d , -
  • R 1 and R 2 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifiuoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -SF 5 , -NR b R c ,
  • Ci_ 6 alkyl C 2 _6 alkenyl, C 2 _ 6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_ 6 )alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci_6)alkyl, C 3 -7 heterocycloalkenyl, C 4 _9 heterobicycloalkyl, heteroaryl, heteroaryl(Ci_6)alkyl,
  • R 3 and R 4 independently represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or -OR a ; or Ci_ 6 alkyl optionally substituted by one or more substituents ;
  • R 5a and R 5b independently represent hydrogen, hydroxy, halogen,
  • heterocycloalkyl heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b and R c independently represent hydrogen or trifluoromethyl; or Ci_ 6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl, homopiperazin-l-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl or (dioxo)thiazinan-4-yl, any of which groups may be optionally substituted by one or more substituents; - -
  • R d represents hydrogen; or Ci_ 6 alkyl, C 3 -7 cycloalkyl, aryl, C 3 -7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
  • R e represents Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • the present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in therapy.
  • the present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated.
  • the present invention provides for the use of a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
  • the present invention provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
  • a modulator of TNFa function comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
  • the present invention provides a method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.
  • Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts, and meglumine salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloro methane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • hydrocarbon solvents such as benzene or toluene
  • chlorinated solvents such as chloroform or dichloro methane
  • alcoholic solvents such as methanol, ethanol or isopropanol
  • ethereal solvents such as diethyl ether or tetrahydrofuran
  • ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • the present invention also includes co-crystals within its scope.
  • co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
  • the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co- crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).
  • Typical examples of co- crystal formers, which may be present in the co-crystal alongside the active pharmaceutical ingredient include Z-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide.
  • the present invention includes within its scope prodrugs of the compounds of formula (I) above.
  • prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched Ci_ 6 alkyl groups, for example Ci_ 4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-bvXy ⁇ , 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as "Ci_ 6 alkoxy", “Ci_ 6 alkylthio", "Ci_ 6 alkylsulphonyl” and "Ci_ 6 alkylamino" are to be construed accordingly.
  • Ci_ 4 alkylene chain refers to a divalent straight or branched alkylene chain containing 1 to 4 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.
  • Suitable C 2 _ 6 alkenyl groups include vinyl and allyl.
  • Suitable C 2 _ 6 alkynyl groups include ethynyl, propargyl and butynyl. - -
  • C3_ 7 cycloalkyl refers to monovalent groups of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo- fused analogues thereof. Suitable C 3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
  • C 4 _ 7 cycloalkenyl refers to monovalent groups of 4 to 7 carbon atoms derived from a partially unsaturated monocyclic hydrocarbon. Suitable C 4 _ 7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • C 4 _9 bicycloalkyl refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon.
  • Typical C 4 _ 9 bicycloalkyl groups include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.2]octanyl and bicyclo [3.3.1] -nonanyl.
  • Typical (C 4 _9)bicycloalkenyl groups include bicyclo[3.1.0]hexenyl.
  • aryl refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci_6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthy lmethy 1.
  • C 3 _ 7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo- furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, dihydroisoindolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro- [l,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl,
  • C 3 _ 7 heterocycloalkenyl refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused - -
  • Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1,2,3,6-tetrahydropyridinyl.
  • C4-9 heterobicycloalkyl corresponds to C4-9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Typical heterobicycloalkyl groups include 3- azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.
  • C 4 _9 spiroheterocycloalkyl refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom.
  • Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro- [2.4]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro- [3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7- azaspiro[3.5]nonanyl and 2,4,8-triazaspiro[4.5]decanyl.
  • heteroaryl refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-£][l,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-£]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-£]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimid
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • the compounds of formula (I) may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereomers.
  • the invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1H.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • Y represents C3-7 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Y represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
  • Y represents optionally substituted C 3 _7 cycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C 3 _7 cycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C 3 _7 cycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C3-7 cycloalkyl. In a second embodiment, Y represents optionally substituted aryl. In one aspect of that embodiment, Y represents unsubstituted aryl. In another aspect of that embodiment, - -
  • Y represents monosubstituted aryl. In a further aspect of that embodiment, Y represents disubstituted aryl.
  • Y represents optionally substituted C 3 _ 7 heterocycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C 3 _ 7 heterocycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C 3 _ 7 heterocycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C 3 _ 7 heterocycloalkyl.
  • Y represents optionally substituted heteroaryl. In one aspect of that embodiment, Y represents unsubstituted heteroaryl. In another aspect of that embodiment, Y represents monosubstituted heteroaryl. In a further aspect of that embodiment, Y represents disubstituted heteroaryl.
  • Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl or pyrazolyl any of which groups may be optionally substituted by one or more substituents.
  • Y represents phenyl, thienyl or thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Y represents phenyl, which may be optionally substituted by one or more substituents.
  • optional substituents which may be present on the moiety Y include one, two or three substituents independently selected from halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, (Ci_6)alkylsulfonyloxy, amino, Ci_ 6 alkyl- amino, di(Ci_6)alkylamino, arylamino, C 2 _ 6 alkylcarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, C 2 _ 6 alkylcarbonyl, C 3 _ 6 cycloalkylcarbonyl, C 3 _ 6 heterocycloalkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, aminocarbonyl, Ci_ 6 alkyl
  • substituents on the moiety Y include fluoro, chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, methylsulfonyloxy, amino, methylamino, tert-butylamino, dimethylamino, phenylamino, acetylamino, methyl- sulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinyl- carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, - -
  • methoxycarbonyl aminocarbonyl, methylaminocarbonyl, dimethylammocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
  • Typical examples of particular substituents on the moiety Y include chloro, fluoro, cyano, methoxy, methylsulphonyl, trifluoromethoxy and difluoromethoxy.
  • Typical values of Y include benzocyclobutenyl, phenyl, (methysulphonyl)phenyl
  • Y include phenyl, (methysulphonyl)phenyl, benzonitrile chlorophenyl, (chloro)(fluoro)phenyl, dichlorophenyl, dimethylphenyl,
  • Y definitive values of Y include (difluoromethoxy)phenyl,
  • Y include (difluoromethoxy)phenyl
  • Y (difluoromethoxy)(cyano)phenyl.
  • Illustrative values of Y include 2-difluoromethoxy-phenyl, 2-difluoromethoxy-5- chloro -phenyl, 2-difluoromethoxy-6-chloro-phenyl, 2-difluoromethoxy-6-fluoro-phenyl, and 2-difluoromethoxy-6-cyano-phenyl, 2-methoxy-phenyl, 3-chloro-phenyl, 2- difluoromethoxy-4,5-difluoro-phenyl, 2-difluoromethoxy-5-fluoro-phenyl and
  • Y 2-difluoromethoxy-4-fluoro-phenyl.
  • Specific values of Y include 2-difluoromethoxy-phenyl, 2-difluoromethoxy-5- chloro -phenyl, 2-difluoromethoxy-6-chloro-phenyl, 2-difluoromethoxy-6-fluoro-phenyl, and 2-difluoromethoxy-6-cyano-phenyl.
  • Y represents 2-(difluoromethoxy)phenyl.
  • Y represents 2-difluoromethoxy-5-chloro- phenyl. - -
  • Z represents a heteroatom; -S(O), -S(0) 2 , -S(0)(N-R d ), -NC(0)R d , - N(CO)-OR d , -NS(0) 2 R d , or -N(R d ) ; or an optionally substituted straight or branched Ci_ 4 alkylene chain;
  • Z represents an optionally substituted straight or branched Ci_ 4 alkylene chain.
  • Z represents an heteroatom. In one aspect of that embodiment Z represents an oxygen. In a second aspect of that embodiment, Z represents a sulphur. In a second embodiment, Z represents -S(O). In a third embodiment, Z represents -S(0) 2 . In a fourth embodiment, Z represents S(0)(N-R d ). In a fifth embodiment, Z represents -NC(0)R d . In a sixth embodiment, Z represents -N(CO)-OR d . In an seventh embodiment, Z represents -NS(0) 2 R d . In an eighth embodiment, Z represents -N(R d ).
  • Z represents an optionally substituted straight or branched Ci_4 alkylene chain.
  • Typical values of Z according to this embodiment include methylene (-CH 2 -), (methyl)methylene, ethylene (-CH 2 CH 2 -), (ethyl)methylene, (dimethyl)- methylene, (methyl)ethylene, propylene (-CH 2 CH 2 CH 2 -), (propyl)methylene and (dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents.
  • Z represents an unsubstituted straight or branched Ci_ 4 alkylene chain.
  • Z represents a monosubstituted straight or branched Ci_ 4 alkylene chain. In a third aspect of this embodiment, Z represents a disubstituted straight or branched Ci_ 4 alkylene chain.
  • Z represents carbonyl
  • Examples of typical substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, hydroxy, oxo, Ci_ 6 alkoxy, aryl, -C(0)R d , -C0 2 R d , -CONR b R c -S(0)(N-R d )R a , and -S0 2 NR b R c .
  • a particular value of Z is methylene.
  • R 1 and R 2 independently represent hydrogen, halogen, cyano, trifluoromethyl; -S(0) 2 (N-R d ), or -C0 2 R d ; or Ci_ 6 alkyl, C 2 _ 6 alkynyl, aryl, C 3 - 7
  • heterocycloalkyl C 3 _ 7 heterocycloalkenyl, heteroaryl, (C 3 _ 7 )heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl-(C 3 _ 7 )heterocycloalkyl-, (C 3 _ 7 )cycloalkyl-heteroaryl-, (C 3 _ 7 )cycloalkyl(Ci_ 6)alkyl-heteroaryl-, (C 4 _ 7 )cycloalkenyl-heteroaryl-, (C 4 _9)bicycloalkyl-heteroaryl-, - -
  • R 2 represents hydrogen, halogen, cyano, nitro, hydroxy
  • Ci_ 6 alkyl optionally substituted by one or more substituents.
  • R 3 represents hydrogen, halogen, cyano, nitro, hydroxy
  • Ci_ 6 alkyl optionally substituted by one or more substituents.
  • R 3 represents hydrogen, halogen, cyano, nitro, hydroxy,
  • Ci_ 6 alkyl optionally substituted by one or more substituents.
  • R 4 represents hydrogen, halogen, cyano, nitro, hydroxy
  • Ci_ 6 alkyl optionally substituted by one or more substituents
  • R 4 represents hydrogen, halogen, cyano, nitro, hydroxy,
  • R 5a represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl
  • R 5b represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl
  • R 5a represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl
  • Ci_ 6 alkyl C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 5b represents hydrogen, hydroxy, halogen, cyano, or trifluoromethyl; or Ci_ 6 alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl; - NR b R c , -NR c C(0)R d , -(CO)NR c R d , -NHS(0) 2 R e , -S-R a , -(SO)-R a , -S(0) 2 R a , -S(0)(N-R d ), -S(0) 2 (N-R d ), -OR a , -C(0)2R d , or -0(CO)-R d -; or Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 , R 2 , R 3 , R 4 R 5a , R 5b and R 6 examples include one, two or three substituents independently selected from halogen, halo- (Ci_6)alkyl, cyano, cyano(Ci_6)alkyl, nitro, nitro(Ci_6)alkyl, Ci_ 6 alkyl, (C 3 -7)cycloalkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C3-7)cycloalkyl-oxy, Ci_ 3 alkylenedioxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_ 6 alkyls
  • An additional example of substituent include C 3 _
  • carboxylic acid isostere or prodrug moiety any functional group, structurally distinct from a carboxylic acid moiety, that will be recognised by a biological system as being similar to, and thus capable of mimicking, a carboxylic acid moiety, or will be readily convertible by a biological system in vivo into a carboxylic acid moiety.
  • a synopsis of some common carboxylic acid isosteres is presented by N.A. Meanwell in J. Med. Chem. , 201 1 , 54, 2529-2591 (cf. in particular Figures 25 and 26).
  • An alternative carboxylic acid isostere is described by N Pemberton et al. in ACS Med. Chem. Lett., 2012, 3, 574-578.
  • suitable carboxylic acid isostere or prodrug moieties represented by ⁇ include the functional groups of formula (i) to (xliii):
  • asterisk (*) represents the site of attachment to the remainder of the molecule; n is zero, 1 or 2;
  • X represents oxygen or sulphur
  • R f represents hydrogen, Ci_ 6 alkyl or -CH 2 CH(OH)CH 2 OH;
  • R g represents Ci_ 6 alkyl, trifhioromethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or
  • R h represents hydrogen, cyano or -C0 2 R d , in which R d is as defined above; and R J represents hydrogen or halogen.
  • n is zero. In another embodiment, n is 1. In a further embodiment, n is 2.
  • X represents oxygen. In another embodiment, X represents sulphur. - -
  • R represents hydrogen. In another embodiment, R represents Ci_6 alkyl, especially methyl. In a further embodiment, R is -CH 2 CH(OH)CH 2 OH.
  • R g represents Ci_ 6 alkyl, especially methyl.
  • R g represents trifluoromethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CF 3 .
  • R g represents trifluoromethyl.
  • R g represents -CH 2 CH 2 F.
  • R g represents -CH 2 CHF 2 .
  • R g represents -CH 2 CF 3 .
  • R g represents -CF 2 CF 3 .
  • R h is hydrogen. In another embodiment, R h represents cyano. In a further embodiment, R h represents -C0 2 R d , especially methoxycarbonyl.
  • R J represents hydrogen. In another embodiment, R J represents halogen, especially chloro.
  • ⁇ represents tetrazolyl, especially a C-linked tetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, in particular a group of formula (xxiv) as depicted above.
  • ⁇ represents Ci_ 6 alkylsulphonylaminocarbonyl, i.e. a moiety of formula (iii) as depicted above wherein R g represents Ci_ 6 alkyl.
  • ⁇ represents Ci_ 6 alkylaminosulphonyl, i.e. a moiety of formula (x) as depicted above wherein R g represents Ci_ 6 alkyl.
  • ⁇ represents (Ci_6)alkylcarbonylaminosulphonyl, i.e. a moiety of formula (v) as depicted above wherein R g represents Ci_ 6 alkyl.
  • R 1 , R 2 , R 3 , R 4 R 5a , R 5b and R 6 examples include fluoro, chloro, bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro, nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoro-ethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, difiuoromethoxy, trifluoromethoxy,
  • dimethylaminoethylamino dimethylaminoethylamino, (dimethylamino)(methyl)propylamino, N- (dimethylaminoethyl)-N-(hydroxyethyl)amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)(hydroxy)propylamino, morpholinylethyl- amino, oxopyrrolidinylmethylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethylamino, methylpyrazolyl- methylamino, acetylamino, N-acetyl-N-methylamino, N-isopropylcarbonyl-N-methyl- amino, acetylaminomethyl, ethenyl
  • Suitable examples of particular substituents on R 1 , R 2 , R 3 , R 4 R 5a , R 5b and R 6 include fluoro, hydroxy, methyl-sulphonyl, methyl, trifluoromethyl, isopropyl,
  • cyclopropyl methoxy, ethoxycarbonyl, methylsulphoximinyl, oxo, carboxy, acetyl, chloro, hydroxyisopropyl, fluoroisopropyl, aminoisopropyl,methylsulphonyl, methylsulphinyl,, cyclopropylsulphonyl and tert-butoxy.
  • R 1 , R 2 , R 3 , R 4 R 5a , R 5b and R 6 include fluoro, hydroxy, methyl-sulphonyl, methyl, trifluoromethyl, isopropyl,
  • R 1 represents hydrogen, halogen, cyano or -C0 2 R d ; or Ci_ 6 alkyl, C 2 _ 6 alkynyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, - -
  • R 1 represents halogen, cyano or -C0 2 R d ; or Ci_ 6 alkyl, C 2 _ 6 alkynyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C 3 -7)heterocycloalkyl- (Ci_6)alkyl-aryl-, heteroaryl(C 3 -7)heterocycloalkyl-, (C 3 -7)cycloalkyl-heteroaryl-,
  • R 1 represents halogen or cyano; or Ci_ 6 alkyl, C 2 _ 6 alkynyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C 3 -7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C 3 -7)heterocycloalkyl-, (C 3 -7)cycloalkyl-heteroaryl-, (C 3 _7)cycloalkyl- (Ci_6)alkyl-heteroaryl-, (C 4 _7)cycloalkenyl-heteroaryl-, (C 4 _9)bicycloalkyl-heteroaryl-, (C 3 -7)heterocycloalkyl-heteroaryl-, (C 3 -7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C 3 -7)hetero
  • R 1 represents aryl, C3-7 heterocycloalkenyl , heteroaryl, (C 3 _ 7)heterocycloalkyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl-, (C 3 _7)cycloalkyl- heteroaryl-, or (C 4 _9)bicycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents aryl, heteroaryl, or (C 3 -7)heterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents hydrogen. In a second embodiment, R 1 represents halogen. In one aspect of that
  • R 1 represents bromo. - -
  • R 1 represents cyano. In a fourth embodiment, R 1 represents -C0 2 R d .
  • R 1 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 1 represents optionally substituted methyl. In another aspect of that embodiment, , R 1 represents optionally substituted ethyl.
  • R 1 represents optionally substituted C 2 _ 6 alkynyl. In one aspect of that embodiment, R 1 represents optionally substituted butynyl.
  • R 1 represents optionally substituted aryl. In one aspect of that embodiment, R 1 represents optionally substituted phenyl. In an eighth embodiment, R 1 represents optionally substituted C 3 _ 7
  • R 1 represents optionally substituted C 3 _ 7
  • R 1 represents optionally substituted pyridine-2( 1 H)-one.
  • R 1 represents optionally substituted heteroaryl.
  • R 1 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl,
  • R 1 represents optionally substituted pyrimidinyl. In a second particular aspect of that embodiment, R 1 represents optionally substituted pyridinyl.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-aryl-.
  • R 1 represents optionally substituted pyrrolidinylmethylphenyl-.
  • R 1 represents optionally substituted piperazinylmethylphenyl-.
  • R 1 represents optionally substituted heteroaryl(C 3 _ 7 )- heterocycloalkyl-. In one aspect of that embodiment, R 1 represents optionally substituted pyridinylpiperazinyl- .
  • R 1 represents optionally substituted (C 3 _ 7 )cycloalkyl- heteroaryl-. In a first aspect of that embodiment, R 1 represents optionally substituted - -
  • R 1 represents optionally substituted cyclohexylpyrazolyl-.
  • R 1 represents optionally substituted cyclohexylpyridinyl-.
  • R 1 represents optionally substituted cyclopropylpyrimidinyl-.
  • R 1 represents optionally substituted cyclobutylpyrimidinyl-.
  • R 1 represents optionally substituted cyclopentylpyrimidinyl-.
  • R 1 represents optionally substituted cyclohexylpyrimidinyl-.
  • R 1 represents optionally substituted cyclohexyl- pyrazinyl-.
  • R 1 represents optionally substituted cyclopropylpyridinylln a fourteenth embodiment, R 1 represents optionally substituted (C 4- 7)-cycloalkenyl-heteroaryl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted pyrrolidinylpyridinyl-.
  • R 1 represents optionally substituted tetrahydropyranylpyridinyl-.
  • R 1 represents optionally substituted piperidinylpyridinyl-.
  • R 1 represents optionally substituted piperazinylpyridinyl-.
  • R 1 represents optionally substituted morpholinylpyridinyl-.
  • R 1 represents optionally substituted thiomorpholinyl- pyridinyl-. In a seventh aspect of that embodiment, R 1 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R 1 represents optionally substituted oxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R 1 represents optionally substituted azetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R 1 represents optionally substituted tetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment, R 1 represents optionally substituted pyrrolidinylpyrimidinyl-.
  • R 1 represents optionally substituted tetrahydropyranyl- pyrimidinyl-.
  • R 1 represents optionally substituted piperidinylpyrimidinyl-.
  • R 1 represents optionally substituted piperazinylpyrimidinyl-.
  • R 1 represents optionally substituted morpholinylpyrimidinyl-.
  • R 1 represents optionally substituted thio morpholinylpyrimidinyl-.
  • R 1 represents optionally substituted azepanylpyrimidinyl-.
  • R 1 represents optionally substituted oxazepanylpyrimidinyl-.
  • R 1 represents optionally substituted diazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R 1 represents optionally substituted thiadiazepanyl- pyrimidinyl-. In a twenty-first aspect of that embodiment, R 1 represents optionally substituted oxetanylpyrazinyl-. In a twenty-second aspect of that embodiment, R 1 represents optionally substituted piperidinylpyrazinyl-. In a twenty-third aspect of that embodiment, R 1 represents optionally substituted tetrahydropyranylpyridinyl. In a twenty- fourth aspect of this embodiment, R 1 represents tetrahydro-thiopyranylpyrimidinyl.
  • R 1 represents (imino)(oxo)thiazinanyl- pyrimidinyl. In a twenty-sixth aspect of this embodiment, R 1 represents (oxo)thiazinanyl- pyrimidinyl. In a twenty-seventh aspect of this embodiment, R 1 represents (dioxo)thiazinanyl-pyrimidinyl.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-heteroaryl-.
  • R 1 represents optionally substituted morpholinylmethylthienyl-.
  • R 1 represents optionally substituted morpholinylethylpyrazolyl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkenyl-heteroaryl-.
  • R 1 represents optionally substituted (C 4- c>)- heterobicycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted 3-azabicyclo[3.2. ljoctanyl-pyrimidinyl.
  • R 1 represents optionally substituted 3-oxa-8-azabicyclo-[3.2. ljoctanyl- pyrimidinyl.
  • R 1 represents optionally substituted 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl-pyrimidnyl.
  • R 1 represents optionally substituted 2,5-diazabicyclo[2.2.1]heptanyl-pyrimidnyl.
  • R 1 represents optionally substituted (C 4- c>)- spiroheterocycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted (C3_7)cycloalkyl- (Ci_6)alkyl-heteroaryl-. In one aspect of that embodiment, R 1 represents optionally substituted cyclohexylmethylpyrimidinyl- . In a twenty-first embodiment, R 1 represents optionally substituted (C4-9)- bicycloalkyl-heteroaryl-. In a particular aspect of this embodiment, R 1 represents optionally substituted bicyclo[3.1.0]hexanyl-pyrimidinyl. - -
  • R 1 represents optionally substituted (C4-9)- bicycloalkenyl-heteroaryl- .
  • R 1 represents hydrogen, bromo, cyano or -C0 2 R d ; or ethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl,
  • pyrrolidinylpyridinyl tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperidinylpyridinyl, piperazinyl-pyridinyl, morpholinylpyridinyl,
  • azetidinylpyrimidinyl tetrahydrofuranylpyrimidinyl, pyrrolidinyl-pyrimidinyl, tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl-pyrimidinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl, oxazepanylpyrimidinyl,
  • R 1 represents 2,5- diazabicyclo[2.2.1]heptanyl-pyrimidinyl or pyridine-2(lH)-one, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents bromo, cyano, phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl- pyrimidinyl, bicyclo[3.1.0]hexenyl-pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperazinyl-pyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl, tetrahydrofuranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl- pyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, 2-oxa-5-
  • R 1 represents bromo, cyano, phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl-pyrimidinyl, bicyclo[3.1.OJhexenyl- pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperazinyl-pyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl,
  • R 1 represents represents 2,5-diazabicyclo[2.2.1]heptanyl-pyrimidinyl or pyridine-2(lH)-one, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.OJhexanyl-pyrimidinyl, - -
  • azetidinylpyrimidinyl tetrahydrofuranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl- pyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, 2-oxa-5- azabicyclo[2.2.1]heptanylpyrimidinyl, 3-azabicyclo[3.2.1]octanyl-pyrimidinyl, 3-oxa-8- azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3,7-dioxa-9-azabicyclo[3.3.1 ]-nonanylpyrimidinyl, epiminofuro [3.2-b]furanyl-pyrimidinyl, 2,5-diazabicyclo[2.2.1]heptanyl-pyrimidinyl or pyridine-2(lH) -one, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl-pyrimidinyl, bicyclo[3.1.0]hexenyl-pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro- thiopyranylpyrimidinyl, piperazinyl-pyridinyl, oxetanylpyrimidinyl,
  • azetidinylpyrimidinyl tetrahydrofuranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl- pyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, 2-oxa-5- azabicyclo[2.2.1 Jheptanylpyrimidinyl, 3-azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3-oxa-8- azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3,7-dioxa-9-azabicyclo[3.3.1 ]-nonanylpyrimidinyl, or epiminofuro [3.2-b]furanyl-pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, halo(Ci_6)alkyl, cyano, cyano(Ci_6)alkyl, nitro(Ci_6)alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkoxy, trifluoroethoxy, carboxy(C3_7)cycloalkyloxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, amino-(Ci_ 6)alkyl, Ci_ 6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Chalky 1]
  • alkylsulphonylamino N- [(C i _6)alky 1] -N- [(C i _6)alkylsulphonyl]amino, bis[(C i _ 6 )alkyl- sulphonyl] amino, N- [(C i _6)alkyl] -N- [carboxy(C i _6)alkyl] amino, carboxy(C 3 _7)cy cloalkyl- amino, carboxy(C 3 _7)cycloalkyl(Ci_6)alkylamino, formyl, C 2 _ 6 alkylcarbonyl, (C 2 _ 6 )alkyl- carbonyloxy(Ci_6)alkyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6
  • alkoxycarbonyl(Ci_6)alkyl morpholinyl(Ci_6)alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl- methylidenyl, aminocarbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl, (Ci_ 6)alkylsulphoximinyl, [(Ci_6)alkyl][N-(Ci_6)alkyl]sulphoximinyl and heteroaryl. Additional - -
  • R 1 examples include difluoromethyl, Ci_ 6 alkylsulphinyl, and (C 3 -7)cycloalkyl sulphonyl.
  • optional substitutents on R 1 include one, two or three substituents independently selected from selected from halogen, hydroxy, trifluoromethyl, Ci_6 alkyl, Ci_ 6 alkoxy , C 2 _ 6 alkylcarbonyl, C 2 _ 6 alkyloxycarbonyl, (hydroxy)Ci_ 6 alkyl , (C 3 -7)cycloalkyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, di(Ci_
  • R 1 Suitable examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, hydroxy, trifluoromethyl, Ci_ 6 alkyl, Ci_ 6 alkoxy , C 2 _ 6 alkylcarbonyl, C 2 _ 6
  • alkyloxycarbonyl (hydroxy)Ci_ 6 alkyl , (C 3 -7)cycloalkyl, Ci_ 6 alkylsulphonyl, (Ci_ 6 )alkylsulphonyl(Ci_6)alkyl, di(Ci_6)alkylaminocarbonyl, (Ci_6)alkylsulphoximinyl, oxo, and carboxy.
  • substituents on R 1 include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, isopropylmethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoro-ethoxy, carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, aminomethyl, amino isopropyl, methylamino, dimethylamino, methoxy ethylamino, N- (hydroxyethyl)-N-(methyl)amino, acetyl
  • substituents on R 1 include chloro, fluroro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, methylsulphonyl, oxo, amino, acetyl, methoxycarbonyl, methylsulphoximinyl, - -
  • substituents on R 1 include chloro, fluroro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, methylsulphonyl, oxo, amino, acetyl, methoxycarbonyl, methylsulphoximinyl, ethoxycarbonyl, n- butoxycarbonyl and tert-butoxy carbonyl.
  • R 1 is substituted by hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 1 is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2-yl.
  • R 1 is substituted by Ci_ 6 alkylsulphonyl. In one aspect of this embodiment, R 1 is substituted by methylsulphonyl.
  • R 1 is substituted by (Ci_6)alkylsulphoximinyl. In one aspect of this embodiment, R 1 is substituted by a methylsulphoximinyl.
  • R 1 include hydrogen, bromo, cyano, -C0 2 R d , methoxycarbonyl- ethyl, ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl, hydroxyphenyl, methyl- sulphonylphenyl, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, aminomethylphenyl, aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl, methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,
  • methylaminopyridinyl dimethyl-aminopyridinyl, methoxyethylaminopyridinyl, N- (hydroxyethyl)-N-(methyl)amino-pyridinyl, methylsulphonylaminopyridinyl,
  • hydroxyisopropylpyrimidinyl methoxypyrimidinyl, carboxycyclobutyloxy-pyrimidinyl, methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, methoxyethylaminopyrimidinyl, N-(carboxyethyl)-N- (methyl)aminopyrimidinyl, carboxycyclopentylaminopyrimidinyl,
  • ethoxycarbonylethylpyrimidinyl hydro xypyrazinyl, hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, carboxy- cyclohexylpyrazolyl, carboxycyclohexylpyridinyl, fluoromethylcyclopropylpyrimidinyl, acetylaminomethylcyclopropylpyrimidinyl, hydroxymethylpyrimidinyl,
  • oxopiperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, carboxyethyl- piperazinylpyrimidinyl, tert-butoxycarbonylpiperazinylpyrimidinyl, tetrazolylmethyl- piperazinylpyrimidinyl, trioxohexahydro-[l ,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl, morpholinylpyrimidinyl, dimethylmorpho linylpyrimidinyl, hydroxymethylmorpholinyl- pyrimidinyl, carboxymorpho linylpyrimidinyl, (carboxy)(methyl)morpho linylpyrimidinyl, carboxymethylmorpho linylpyrimidinyl, thiomorpholinylpyrimidinyl, oxo- thiomorpholinylpyrimidinyl, dioxo-thiomorph
  • morpholinylethylpyrazolyl isopropylmethylpyrazolyl, carboxy-3 - azabicyclo[3.1.0]hexanylpyridinyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl, carboxy-3 -azabicyclo [3.1.0]hexanylpyrimidinyl, (carboxy)(methyl)-3 - azabicyclo[3.1.0]hexanylpyrimidinyl, methoxycarbonyl-3 - azabicyclo[3.1.0]hexanylpyrimidinyl, ethoxycarbonyl-3 -azabicyclo [3.1.OJhexanyl- pyrimidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl, carboxy-2-oxa-5-azabicyclo- [2.2.1 Jheptanylpyrimidinyl, carboxy-3 -azabicyclo [3.1.1 Jheptanylpyrimi
  • R 1 includes difluorocyclobutanyl- pyrimidinyl, difluoromethyl-pyrimidinyl, cyclopropyl-pyrimidinyl, amino isopropyl- pyrimidinyl,(hydroxy)cyclopropyl-pyrimidinyl, (difluoro)(hydroxy)cyclobutyl- pyrimidinyl, (methyl)cyclobutane-diol, (hydroxy)(methyl)cyclohexyl-pyrimidinyl, (methyl)cyclohexane-diol, (chloro)(methoxy)pyridinyl, methylsulphinyl-phenyl, cyclopropylsulphonyl-phenyl, tert-butoxy-pyridinyl, methylsulphoximinylpyridinyl, piperazinyl-2-one-pyrimidinyl, (methyl
  • R 1 Appropriate values of R 1 include bromo, cyano, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, (di-(trifluoromethyl))(hydroxy)phenyl, chloropyridinyl, tetrahydropyranylpyridinyl, hydroxyisopropylpyridinyl, hydroxymethylpyridinyl, methoxypyridinyl, isopropoxypyridinyl, isopropylpyrimidinyl,
  • piperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, tert- butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl, - -
  • R 1 Illustrative values of R 1 include bromo, cyano, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, (di-(trifluoromethyl))(hydroxy)phenyl, chloropyridinyl, tetrahydropyranylpyridinyl, hydroxyisopropylpyridinyl, hydroxymethylpyridinyl, methoxypyridinyl, isopropoxypyridinyl, isopropylpyrimidinyl,
  • piperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, tert- butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl,
  • R 2 represents hydrogen, halogen, cyano, nitro, hydroxy,
  • R 2 trifluoromethyl, trifluoromethoxy; or -OR a ; or an optionally substituted Ci_ 6 alkyl.
  • optional substituents on R 2 include C 2 _ 6 alkoxycarbonyl.
  • Typical examples of particular substituents on R 2 include ethoxycarbonyl.
  • R 2 represents hydrogen. In a second embodiment, R 2 represents halogen. In one aspect of that embodiment, R 2 represents fluoro. In another aspect of that embodiment, R 2 represents chloro. In a third embodiment, R 2 represents cyano. In a fourth embodiment, R 2 represents nitro. In a fifth embodiment, R 2 represents hydroxy. In a sixth embodiment, R 2 represents trifluoromethyl. In a seventh embodiment, R 2 represents trifluoromethoxy. In an eighth embodiment, R 2 represents -OR a . In a ninth embodiment, R 2 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 2 represents unsubstituted methyl. In another aspect of that embodiment, R 2 represents unsubstituted ethyl. In a further aspect of that embodiment, R 2 represents monosubstituted methyl or monosubstituted ethyl.
  • Typical values of R 2 include hydrogen, fluoro, chloro, trifluoromethyl,
  • R 2 include hydrogen and fluoro.
  • R 3 represents hydrogen, halogen or Ci_ 6 alkyl. - -
  • R 3 represents hydrogen. In a second embodiment, R 3 represents halogen. In one aspect of that embodiment, R 3 represents fluoro.
  • R 3 represents Ci_ 6 alkyl. In one aspect of that embodiment, R 3 represents unsubstituted Ci_ 6 alkyl. In a second aspect of that embodiment, R 3 represents substituted Ci_ 6 alkyl. In a particular aspect of this embodiment, R 3 represents methyl. In another particular aspect of that embodiment, R 3 represents ethyl.
  • R 3 represents hydrogen
  • R 4 represents hydrogen, halogen or Ci_ 6 alkyl.
  • R 4 represents hydrogen.
  • R 4 represents halogen.
  • R 4 represents fluoro.
  • R 4 represents Ci_ 6 alkyl.
  • R 4 represents unsubstituted Ci_ 6 alkyl.
  • R 4 represents substituted Ci_6 alkyl.
  • R 4 represents methyl.
  • R 4 represents ethyl.
  • R 4 represents hydrogen
  • R 5a represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl; - NR b R c , -NR c C(0)R d , -(CO)NR c R d , -NHS(0) 2 R e , -S-R a , -(SO)-R a , -S(0) 2 R a , -S(0)(N-R d ), -S(0) 2 (N-R d ), -OR a , -C(0)2R d , or -0(CO)-R d -; or Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 5a represents hydrogen, hydroxy, halogen, trifluoromethyl; -NR b R c , S(0) 2 R a , -OR a , 0-(CO)_R d or -NR c C(0)R d ; or Ci_ 6 alkyl any of which groups may be optionally substituted.
  • R 5a represents hydrogen, hydroxy, halogen,
  • Suitable examples of optional substituents on R 5a include one, two or three substituents independently selected from halogen, hydroxy, trifluoromethyl, Ci_ 6 alkyl, Ci_6 alkoxy , C 2 _ 6 alkylcarbonyl, C 2 _ 6 alkyloxycarbonyl, (hydroxy)Ci_ 6 alkyl , (C 3 _ 7)cycloalkyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, di(Ci_
  • substituents on R 5a include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl, ethyl, isopropyl, isopropylmethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoro-ethoxy, carboxycyclobutyloxy, methylthio, methylsulphonyl,
  • aminoisopropyl methylamino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N- (methyl)amino, acetylaminomethyl, methylsulphonylamino, N-methyl-N- (methylsulphonyl)amino, bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino, carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,
  • ethoxycarbonyl n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl, ethoxycarbonyl- methylidenyl, methylsulphonylaminocarbonyl, acetylaminosulphonyl, methoxyamino- carbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl, amino- sulphonyl, methylsulphoximinyl and (methyl)(N-methyl)sulphoximinyl.
  • R 5a represents hydrogen. In a second embodiment, R 5a represents hydroxy. In a third embodiment, R 5a represents halogen. In one aspect of this embodiment, R 5a represents fluoro. In a fourth embodiment, R 5a represents
  • R 5a represents -NR b R c . In one aspect of that embodiment, R 5a represents -NH 2 . In a sixth embodiment, R 5a represents -NR c C(0)R d . In a seventh embodiment, R 5a represents -C(0)-NR c R d . In an eighth embodiment, R 5a represents -NHS(0) 2 R e . In a ninth embodiment, R 5a represents -S-R a . In a tenth embodiment, R 5a represents -S(0)-Ra. In an eleventh embodiment, R 5a represents - S(0) 2 R a . In a particular aspect of this embodiment, R 5a represents -S(0) 2 -CH3.
  • R 5a represents -S(0)(N-R d )R a .
  • R 5a represents -S(0) 2 (N-R d ).
  • R 5a represents -OR a .
  • R a is a Ci_ 6 alkyl.
  • R a is an aryl.
  • R a is an heteroaryl.
  • R 5a represents -0-(CO)-R d .
  • R 5a represents -O- (CO)-CH 3 .
  • R 5a represents -C(0)-OR d .
  • R 5a represents optionally substituted Ci_ 6 alkyl.
  • R 5a represents substituted Ci_ 6 alkyl.
  • R 5a represents unsubtituted Ci_ 6 alkyl. In a particular aspect of this embodiment, R 5a represents methyl. In an eighteenth embodiment, R 5a represents an optionally substituted C 2 -6 alkynyl. In a nineteenth embodiment, R 5a represents an optionally substituted heteroaryl. In a twentieth embodiment R 5a represents an optionally substituted aryl. In a twenty- first embodiment, R 5a represents an optionally substituted C 2 -6 alkenyl.
  • R 5a represents cyano
  • R 5b represents hydrogen, hydroxy, halogen, cyano, trifluoromethyl - NR b R c , -NR c C(0)R d , -(CO)NR c R d , -NHS(0) 2 R e , -S-R a , -(SO)-R a , -S(0) 2 R a , -S(0)(N-R d ), -S(0) 2 (N-R d ), -OR a , -C(0) 2 R d , or -0(CO)-R d -; or Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 5b represents hydrogen, hydroxy, halogen, trifluoromethyl -NR b R c , S(0) 2 R a , -OR a , or 0-(CO)_R d ; or Ci_ 6 alkyl any of which groups may be optionally substituted.
  • Suitable examples of optional substituents on R 5b include one, two or three substituents independently selected from halogen, hydroxy, trifluoromethyl, Ci_ 6 alkyl, Ci_ 6 alkoxy , C 2 -6 alkylcarbonyl, C 2 -6 alkyloxycarbonyl, (hydroxy)Ci_ 6 alkyl , (C3_7)cycloalkyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, di(Ci_6)alkylaminocarbonyl, oxo, and carboxy.
  • substituents on R 5b include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl, ethyl, isopropyl, isopropylmethyl,
  • R 5b represents hydrogen. In a second embodiment, R 5b represents hydroxy. In a third embodiment, R 5b represents halogen. In one aspect of this embodiment, R 5b represents fluoro. In a fourth embodiment, R 5b represents
  • R 5b represents -NR b R c . In one aspect of that embodiment, R 5b represents -NH 2 . In a sixth embodiment, R 5b represents -NR c C(0)R d . In a seventh embodiment, R 5b represents -C(0)-NR c R d . In an eighth embodiment, R 5b represents -NHS(0) 2 R e . In a ninth embodiment, R 5a represents -S-R a . In a tenth embodiment, R 5b represents -S(0)-R a . In an eleventh embodiment, R 5b represents - S(0) 2 R a . In a particular aspect of this embodiment, R 5b represents -S(0) 2 -CH3.
  • R 5b represents -S(0)(N-R d )R a .
  • R 5b represents -S(0) 2 (N-R d ).
  • R 5b represents -OR a .
  • Ra is a Ci_ 6 alkyl.
  • R a is an aryl.
  • R a is an heteroaryl.
  • R 5b represents -0-(CO)-R d .
  • R 5a represents -O- (CO)-CH 3 .
  • -C(0)-OR d .
  • R 5b represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 5b represents substituted Ci_ 6 alkyl. In a second aspect of this embodiment, R 5b represents unsubtituted Ci_ 6 alkyl. In a particular aspect of this embodiment, R 5b represents methyl. In an eighteenth embodiment, R 5b represents an optionally substituted C 2 - 6 alkynyl. In a nineteenth embodiment, R 5b represents an optionally substituted heteroaryl. In a twentieth embodiment R 5b represents an optionally substituted aryl. In a twenty- first embodiment, R 5b represents an optionally substituted C 2 - 6 alkenyl. In a twenty-second embodiment, R 5b represents cyano.
  • R 5b represents hydrogen or methyl.
  • R a and R when taken together with the carbon to which they are attached represent a carbonyl.
  • R 5a and R 5b when taken together with the carbon to which they are attached represent a thiocarbonyl.
  • Illustrative values of R 5a include hydrogen, hydroxy, fluoro, trifluoromethyl, - N(CH 3 ) 2 , -NH(CO)CH 3 , -S0 2 -CH 3 , -0-(CO)-CH 3 , methyl, methoxy, pyridinemethyloxy- , benzyloxy, (methoxycarbonyl)methyloxy-, (ethyloxycarbonyl)methyloxy-, (tert- butoxycarbonyl)methyloxy-, (hydroxycarbonyl)methyloxy and cyanomethyloxy.
  • Selected values of R 5a include hydrogen, hydroxy, fluoro, trifluoromethyl, - N(CH 3 ) 2 , -NH(CO)CH 3 , -S0 2 -CH 3 , -0-(CO)-CH 3 , methyl and methoxy.
  • R 5b Selected values of R 5b include hydrogen, hydroxy, fluoro, trifluoromethyl, - N(CH 3 ) 2 , -NH(CO)CH 3 , -S0 2 -CH 3 , -0-(CO)-CH 3 , methyl and methoxy.
  • R 5a is as defined above and R 5b represents hydrogen.
  • R 5a is hydroxy
  • R 5a is as defined above and R 5b represents Ci_ 4 alkyl, preferably methyl. In a particular aspect of this embodiment, R 5a is hydroxy.
  • R 6 represents hydrogen, hydroxy, halogen, trifluoromethyl, -NR b R c , - NR c C(0)R d , -NHS(0) 2 R e ,-S(0) 2 R a , -S(0)(N-R d )R a or -0-(CO)_R d ; or Ci_ 6 alkoxy, Ci_ 6 alkyl, C 2 _ 6 alkynyl, heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents hydrogen, hydroxy, halogen, or trifluoromethyl.
  • R 6 represents hydrogen.
  • R 6 and Y together with the carbon to which they are attached form a C 3 _ 7 cycloalkyl.
  • R 6 and Y together with the carbon to which they are attached form a C 3 _ 7 heterocycloalkyl.
  • R 6 and Y together with the carbon to which they are attached form a dihydrobenzofuran.
  • R 6 and Y together with the carbon to which they are attached form a dihydroisoindole.
  • R 6 and Y together with the carbon to which they are attached form a dihydroisoindolone.
  • Suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, hydroxy, hydroxy(Ci_ 6 )alkyl, amino(Ci_6)alkyl, cyano, trifluoromethyl, oxo, C 2 -6 alkylcarbonyl, carboxy, C 2 -6 alkoxycarbonyl, C 2 -6 alkylcarbonyloxy, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, phenylamino, pyridinylamino, C 2 -6 alky
  • Typical examples of specific substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxy ethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl,
  • R a represents Ci_ 6 alkyl, aryl(Ci_ 6 )alkyl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Illustrative examples of suitable substituents on R a include Ci_ 6 alkoxy, oxo, cyano and C 2 -6 alkoxycarbonyl.
  • R a Selected examples of suitable substituents on R a include Ci_ 6 alkoxy and oxo. Selected examples of specific substituents on R a include methoxy and oxo. - -
  • R a represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci_ 6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci_ 6 alkyl. In a first particular aspect of this embodiment R a represents methoxyethyl. In a second particular aspect of this embodiment, R a represents methoxycarbonyl. In a third aspect of this embodiment, R a represents ethoxycarbonyl. In a fourth aspect of this embodiment, R a represents tert-butoxy-carbonyl. In a fifth aspect of this embodiment, R a represents carboxy-methyl. In another embodiment, R a represents optionally substituted aryl.
  • R a represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R a represents monosubstituted aryl, especially methylphenyl. In another embodiment, R a represents optionally substituted aryl(Ci_6)alkyl, ideally unsubstituted aryl(Ci_6)alkyl, especially benzyl. In a further embodiment, R a represents optionally substituted heteroaryl. In a further embodiment, R a represents optionally substituted heteroaryl(Ci_6)alkyl, e.g. dioxoisoindolylpropyl or pyridinyl-methyl . In a further embodiment, R a represents C 3 _ 7 cycloalkyl. In another further embodiment, R a represents C 3 _ 7 heterocycloalkyl.
  • R a Illustrative values of R a include methyl, methoxyethyl, benzyl, dioxoisoindolylpropyl, pyridinylmethyl, methoxycarbonylmethyl, carboxymethyl, ethoxycarbonylmethyl, and tert-butoxy-carbonylmethyl Specific values of R a include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.
  • R b represents hydrogen or trifluoromethyl; or Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, C 3 _ 7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or Ci_ 6 alkyl, aryl(Ci_ 6 )alkyl, C 3 _ 7 heterocycloalkyl or C 3 _ 7 heterocycloalkyl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b examples include hydrogen and Ci_ 6 alkyl.
  • R b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, - -
  • R b include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R b Selected examples of suitable substituents on R b include Ci_ 6 alkoxy, Ci_ 6 alkylthio, Ci_6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, hydroxy, cyano, C 2 -6 alkoxycarbonyl, di- (Ci_6)alkylamino and C 2 -6 alkoxy carbonylamino.
  • R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.
  • R b include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino - ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci_ 6 alkyl, especially methyl. Selected values of R c include hydrogen; or Ci_ 6 alkyl, C3-7 cycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R c represents hydrogen, Ci_ 6 alkyl or C3-7 cycloalkyl.
  • R c include hydrogen; or methyl, eye lo butyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R c Selected examples of suitable substituents on R c include C 2 -6 alkylcarbonyl and C2-6 alkoxycarbonyl.
  • R c Selected examples of specific substituents on R c include acetyl and tert- butoxycarbonyl.
  • Specific values of R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
  • R c represents hydrogen or Ci_ 6 alkyl.
  • R c is hydrogen.
  • R c represents Ci_ 6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the moiety -NR b R c may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl,
  • homomorpholin-4-yl homopiperazin-l-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl or (dioxo)thiazinan-4-yl, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci_ 6 alkyl, Ci_ 6 alkylsulphonyl, hydroxy, hydroxy(Ci_ 6 )alkyl, amino(Ci_6)alkyl, cyano, oxo, C 2 -6 alkylcarbonyl, carboxy, C 2 -6 alkoxycarbonyl, amino, C 2 -6 alkylcarbonyl- amino, C 2 -6 alkylcarbonylamino(Ci_6)alkyl, C 2 -6 alkoxycarbonylamino, Ci_ 6 alkyl- sulphonylamino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
  • heterocyclic moiety -NR b R c include azetidin-l-yl, hydroxyazetidin- 1 -yl, hydroxymethylazetidm- 1 -yl, (hydro xy)(hydroxymethyl)azetidin- 1 - yl, aminomethyl-azetidin-l-yl, cyanoazetidin-l-yl, carboxyazetidin-l-yl, aminoazetidin-1- yl, aminocarbonylazetidin-l-yl, pyrrolidin-l-yl, aminomethylpyrrolidin-l-yl,
  • oxopyrrolidin-l-yl acetylamino methylpyrrolidin- 1-yl, tert- butoxycarbonylaminopyrrolidin- 1 -yl, oxo-oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, - -
  • thiazolidin-3-yl oxothiazolidin-3-yl, dioxo-isothiazolidin-2-yl, piperidin-l-yl, hydroxypiperidin- 1 -yl, hydroxymethylpiperidin- 1 -yl, aminopiperidin- 1 -yl,
  • R d represents hydrogen; or Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable values for R d include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, eye lo butyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R d Selected examples of suitable substituents on R d include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, oxo, C 2 _ 6 alkylcarbonyloxy and di(Ci_6)alkylamino.
  • R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
  • R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci_ 6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R d ideally represents substituted Ci_ 6 alkyl, e.g. substituted methyl or substituted ethyl, including
  • R d represents optionally substituted aryl. In one aspect of that embodiment, R d represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R d represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, R d represents disubstituted aryl, e.g. dimethoxyphenyl.
  • R d represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl.
  • R d represents optionally substituted C3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl. - -
  • R represents optionally substituted C 3 _ 7 heterocycloalkyl, e.g. thiazolidinyl or oxo-thiazolidinyl.
  • R d selected examples include hydrogen, methyl, acetoxy- methyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, eye lo butyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
  • R d Particular examples of selected values for R d include hydrogen and methyl.
  • R e represents Ci_ 6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
  • R e Selected examples of suitable substituents on R e include Ci_ 6 alkyl, especially methyl.
  • R e represents optionally substituted Ci_ 6 alkyl, ideally unsubstituted Ci_ 6 alkyl, e.g. methyl or propyl, especially methyl.
  • R e represents optionally substituted aryl.
  • R e represents unsubstituted aryl, especially phenyl.
  • R e represents monosubstituted aryl, especially methylphenyl.
  • R e represents optionally substituted heteroaryl.
  • Selected values of R e include methyl, propyl and methylphenyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • R 1 represents halogen or cyano
  • heterocycloalkyl C 3 _ 7 heterocycloalkenyl, heteroaryl, (C 3 _ 7 )heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C 3 _ 7 )heterocycloalkyl-, (C 3 _ 7 )cycloalkyl-heteroaryl-, (C 3 _ 7 )cycloalkyl-(Ci_ - - -
  • R 2 represents hydrogen, halogen, trifluoromethyl or cyano; or an optionally substituted Ci_ 6 alkyl.
  • Z represents an oxygen atom or a sulphur atom; or -S(O), -N(R d ); or an optionally substituted straight or branched Ci_4 alkylene chain.
  • R 5a represents hydrogen, hydroxy, halogen, cyano, or trifluoromethyl; or -NR b R c , -NR c C(0)R d , -(CO)NR c R d , -NHS(0) 2 R e , -S-R a , -(SO)-R a , -S(0) 2 R a , -S(0)(N-R d ), - S(0) 2 (N-R d ), -OR a , -C(0) 2 R d , -0(CO)-R d -; Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
  • R 1 , R 2 , R 5a and R 5b examples include one, two or three substituents independently selected from halogen, halo- (Ci_6)alkyl, cyano, cyano(Ci_6)alkyl, nitro, nitro(Ci_6)alkyl, Ci_ 6 alkyl, (C 3 _ 7 )cycloalkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C 3 _ 7 )cycloalkyl-oxy, Ci_ 3 alkylenedioxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_6 alkylsulphinyl, Ci_
  • An additional example of substituent include C 3 _
  • R 1 , R 2 , R 5a and R 5b examples include fluoro, chloro, bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro, nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoro-ethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,
  • Suitable examples of particular substituents on R 1 , R 2 , R 5b and R 6 include fluoro, hydroxy, methyl-sulphonyl, methyl, trifluoromethyl, isopropyl, cyclopropyl, methoxy, ethoxycarbonyl, methylsulphoximinyl, oxo, carboxy, acetyl, chloro, hydroxyisopropyl, fluoroisopropyl, aminoisopropyl,methylsulphonyl, methylsulphinyl,, cyclopropylsulphonyl and tert-butoxy.
  • R 1 represents Ci_ 6 alkyl, C 2 _ 6 alkynyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C 3 _ 7 )heterocycloalkyl-, (C 3 - 7 )cycloalkyl-heteroaryl-, (C 3 _ 7 )cycloalkyl- (Ci_6)alkyl-heteroaryl-, (C 4 _ 7 )cycloalkenyl-heteroaryl-, (C 4 _9)bicycloalkyl-heteroaryl-, (C 3 _ 7 )heterocycloalkyl-heteroaryl-, (C 3 _ 7 )heterocycloalkyl(Ci_6)alkyl-heteroaryl-,
  • R 1 represents aryl, C3_ 7 heterocycloalkenyl, heteroaryl, (C3- 7 )heterocycloalkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl-, (C 3 _ 7 )cycloalkyl- - -
  • heteroaryl- or (C4_9)bicycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents aryl, heteroaryl, (C 3 - 7 )cycloalkyl-heteroaryl or (C 3 _ 7 )heterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen. In one aspect of that embodiment, R 1 represents bromo. In a second embodiment, R 1 represents cyano. In a third embodiment,
  • R 1 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 1 represents optionally substituted methyl. In another aspect of that embodiment, R 1 represents optionally substituted ethyl. In a fourth embodiment, R 1 represents optionally substituted C 2 _ 6 alkynyl. In one aspect of that embodiment, R 1 represents optionally substituted butynyl. In a fifth embodiment, R 1 represents optionally substituted aryl. In one aspect of that embodiment, R 1 represents optionally substituted phenyl. In sixth embodiment, R 1 represents optionally substituted C 3 _ 7 heterocycloalkyl. In a seventh embodiment, R 1 represents optionally substituted C 3 _ 7 heterocycloalkenyl. In one aspect of this embodiment, R 1 represents optionally substituted pyridine-2(lH)-one.
  • R 1 represents optionally substituted heteroaryl.
  • R 1 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl,
  • R 1 represents optionally substituted pyrimidinyl. In a second particular aspect of that embodiment, R 1 represents optionally substituted pyridinyl
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-aryl-.
  • R 1 represents optionally substituted pyrrolidinylmethylphenyl-.
  • R 1 represents optionally substituted piperazinylmethylphenyl-.
  • R 1 represents optionally substituted heteroaryl(C 3 _ 7 )- heterocycloalkyl-. In one aspect of that embodiment, R 1 represents optionally substituted pyridinylpiperazinyl-.
  • R 1 represents optionally substituted (C 3 _ 7 )cycloalkyl- heteroaryl-. In a first aspect of that embodiment, R 1 represents optionally substituted - -
  • R 1 represents optionally substituted cyclohexylpyrazolyl-.
  • R 1 represents optionally substituted cyclohexylpyridinyl-.
  • R 1 represents optionally substituted cyclopropylpyrimidinyl-.
  • R 1 represents optionally substituted cyclobutylpyrimidinyl-.
  • R 1 represents optionally substituted cyclopentylpyrimidinyl-.
  • R 1 represents optionally substituted cyclohexylpyrimidinyl-.
  • R 1 represents optionally substituted cyclohexyl- pyrazinyl-.
  • R 1 represents optionally substituted cyclopropylpyridinyl.
  • R 1 represents (C3_7)cycloalkyl-(Ci_6)alkyl-heteroaryl-.
  • R 1 represents optionally substituted (C 4-7 )- cycloalkenyl-heteroaryl- .
  • R 1 represents optionally substituted (C4-9)- bicycloalkyl-heteroaryl- .
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted pyrrolidinylpyridinyl-.
  • R 1 represents optionally substituted tetrahydropyranylpyridinyl-.
  • R 1 represents optionally substituted piperidinylpyridinyl-.
  • R 1 represents optionally substituted piperazinylpyridinyl-.
  • R 1 represents optionally substituted morpholinylpyridinyl-. In a sixth aspect of that embodiment, R 1 represents optionally substituted thiomorpholinyl- pyridinyl-. In a seventh aspect of that embodiment, R 1 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R 1 represents optionally substituted oxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R 1 represents optionally substituted azetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R 1 represents optionally substituted tetrahydrofuranylpyrimidinyl-.
  • R 1 represents optionally substituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of that embodiment, R 1 represents optionally substituted tetrahydropyranyl- pyrimidinyl-. In a thirteenth aspect of that embodiment, R 1 represents optionally substituted piperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R 1 represents optionally substituted piperazinylpyrimidinyl-. In a fifteenth aspect of that - -
  • R 1 represents optionally substituted morpholinylpyrimidinyl-. In a sixteenth aspect of that embodiment, R 1 represents optionally substituted thio morpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment, R 1 represents optionally substituted azepanylpyrimidinyl-. In an eighteenth aspect of that embodiment, R 1 represents optionally substituted oxazepanylpyrimidinyl-. In a nineteenth aspect of that embodiment, R 1 represents optionally substituted diazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R 1 represents optionally substituted thiadiazepanyl- pyrimidinyl-.
  • R 1 represents optionally substituted oxetanylpyrazinyl-.
  • R 1 represents optionally substituted piperidinylpyrazinyl-.
  • R 1 represents optionally substituted tetrahydropyranylpyridinyl.
  • R 1 represents tetrahydro-thiopyranylpyrimidinyl.
  • R 1 represents (imino)(oxo)thiazinanyl-pyrimidinyl.
  • R 1 represents (oxo)thiazinanyl-pyrimidinyl. In twenty-seventh aspect of that embodiment, R 1 represents and (dioxo)thiazinanyl-pyrimidinyl.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-heteroaryl-.
  • R 1 represents optionally substituted morpholinylmethylthienyl-.
  • R 1 represents optionally substituted morpholinylethylpyrazolyl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkenyl-heteroaryl- .
  • R 1 represents optionally substituted (C 4- c>)- heterobicycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted 3-azabicyclo[3.2.1]octanyl-pyrimidinyl.
  • R 1 represents optionally substituted 3-oxa-8-azabicyclo-[3.2.1]octanyl- pyrimidinyl.
  • R 1 represents optionally substituted 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl-pyrimidnyl.
  • R 1 represents optionally substituted 2,5-diazabicyclo[2.2.1]heptanyl-pyrimidnyl.
  • R 1 represents optionally substituted (C 4- c>)- spiroheterocycloalkyl-heteroaryl-. - -
  • R 1 represents optionally substituted (C 4- c>)- bicycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted bicyclo[3.1.0]hexanyl-pyrimidinyl.
  • R 1 represents bromo, cyano; or ethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, cyclohexylpyrazolyl, cyclohexylpyridinyl, cyclopropylpyrimidinyl, cyclobutylpyrimidmy
  • pyrrolidinylpyridinyl tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperidinylpyridinyl, piperazinyl-pyridinyl, morpholinylpyridinyl,
  • azetidinylpyrimidinyl tetrahydrofuranylpyrimidinyl, pyrrolidinyl-pyrimidinyl, tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl-pyrimidinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl, oxazepanylpyrimidinyl,
  • R 1 represents 2,5- diazabicyclo[2.2.1]heptanyl-pyrimidinyl or pyridine-2(lH)-one, which may be optionally substituted by one or more substituents.
  • R 1 represents bromo, cyano, phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl- pyrimidinyl, bicyclo[3.1.0]hexenyl-pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperazinyl-pyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl, tetrahydrofuranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl- pyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, 2-oxa-5-
  • R 1 represents bromo, cyano, phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl-pyrimidinyl, bicyclo[3.1.OJhexenyl- pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperaziny
  • R 1 represents represents 2,5-diazabicyclo[2.2.1]heptanyl-pyrimidinyl or pyridine-2(lH)-one, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.OJhexanyl-pyrimidinyl, - -
  • azetidinylpyrimidinyl tetrahydrofuranylpyrimidinyl, piperidinylpyrimidinyl, piperazinyl- pyrimidinyl, morpholinyl-pyrimidinyl, thiomorpholinylpyrimidinyl, 2-oxa-5- azabicyclo[2.2.1 Jheptanylpyrimidinyl, 3-azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3-oxa-8- azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3,7-dioxa-9-azabicyclo[3.3.1 ]-nonanylpyrimidinyl, epiminofuro [3.2-b]furanyl-pyrimidinyl, , (imino)(oxo)thiazinanyl-pyrimidinyl,
  • R 1 represents phenyl, pyridinyl, dihydropyridinyl, pyrimidinyl, cyclobutylpyrimidinyl, cyclopropylpyridinyl, bicyclo[3.1.0]hexanyl-pyrimidinyl, bicyclo[3.1.0]hexenyl-pyrimidinyl, pyrimidinyl, tetrahydropyranylpyridinyl, tetrahydro-thiopyranylpyrimidinyl, piperazinyl-pyridinyl, oxetanylpyrimidinyl, azetidin
  • thiomorpholinylpyrimidinyl 2-oxa-5 -azabicyclo [2.2.1 Jheptanylpyrimidinyl, 3- azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3-oxa-8-azabicyclo[3.2.1 Joctanyl-pyrimidinyl, 3,7- dioxa-9-azabicyclo[3.3.1]-nonanylpyrimidinyl, epiminofuro [3.2-b]furanyl-pyrimidinyl, , (imino)(oxo)thiazinanyl-pyrimidinyl, (oxo)thiazinanyl-pyrimidinyl or (dioxo)thiazinanyl- pyrimidinyl,any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, halo(Ci_6)alkyl, cyano, cyano(Ci_
  • R 1 methylidenyl, (Ci_6)alkylsulphoximinyl and [(Ci_6)alkyl][N-(Ci_6)alkyl]sulphoximinyl.
  • Additional examples of optional substituents on R 1 include one, two or three substituents independently selected difluoromethyl, Ci_ 6 alkylsulphinyl, and (C 3 -7)cycloalkyl sulphonyl.
  • optional substitutents on R 1 include one, two or three substituents independently selected from halogen, hydroxy, trifluoromethyl, Ci_ 6 alkyl, Ci_6 alkoxy , C 2 _ 6 alkylcarbonyl, C 2 _ 6 alkyloxycarbonyl, (hydroxy)Ci_ 6 alkyl , (C 3 _ 7)cycloalkyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, di(Ci_
  • Suitable examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, hydroxy, Ci_ 6 alkyl, Ci_ 6 alkoxy , Ci_ 6 alkylcarbonyl, (hydroxy)Ci_ 6 alkyl , (C 3 -7)cycloalkyl, Ci_ 6 alkylsulphonyl, (Ci_
  • substituents on R 1 include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl, ethyl, isopropyl, cyclopropyl, isopropylmethyl, trifluoromethyl, trif uoroethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoro-ethoxy, carboxy cyclobutyloxy, methylthio,
  • substituents on R 1 include chloro, fluroro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, - -
  • substituents on R 1 include chloro, fluroro, methyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, methylsulphonyl, methylsulphoximinyl, oxo, amino, acetyl, methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl and tert- butoxycarbonyl
  • R 1 is substituted by hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 1 is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2- yl.
  • R 1 is substituted by hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 1 is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2-yl.
  • R 1 is substituted by Ci_ 6 alkylsulphonyl. In one aspect of this embodiment, R 1 is substituted by methylsulphonyl. In a third particular embodiment R 1 is substituted by a halogen. In one aspect of this embodiment, R 1 is substituted by a fluoro.
  • R 1 is substituted by (Ci_6)alkylsulphoximinyl. In one aspect of this particular embodiment, R 1 is substituted by methylsulphoximinyl.
  • R 1 selected values include bromo, cyano, methoxycarbonyl-ethyl,
  • ethoxycarbonylethyl hydroxybutynyl, chlorophenyl, hydroxyphenyl, methyl- sulphonylphenyl, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, aminomethylphenyl, aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl, methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,
  • methylaminopyridinyl dimethyl-aminopyridinyl, methoxyethylaminopyridinyl, N- (hydroxyethyl)-N-(methyl)amino-pyridinyl, methylsulphonylaminopyridinyl,
  • hydroxyisopropylpyrimidinyl methoxypyrimidinyl, carboxycyclobutyloxy-pyrimidinyl, methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, methoxyethylaminopyrimidinyl, N-(carboxyethyl)-N- (methyl)aminopyrimidinyl, carboxycyclopentylaminopyrimidinyl,
  • ethoxycarbonylethylpyrimidinyl hydroxypyrazinyl, hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, carboxy- cyclohexylpyrazolyl, carboxycyclohexylpyridinyl, fluoromethylcyclopropylpyrimidinyl, acetylaminomethylcyclopropylpyrimidinyl, hydroxymethylpyrimidinyl,
  • piperazinylpyridinyl (methyl)(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl, trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl, methyl- sulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl, acetylpiperazinylpyridinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyridinyl, methylpiperazinylpyridinyl, carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,
  • oxopiperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, carboxyethyl- piperazinylpyrimidinyl, tert-butoxycarbonylpiperazinylpyrimidinyl, tetrazolylmethyl- piperazinylpyrimidinyl, trioxohexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl, morpholinylpyrimidinyl, dimethylmorpho linylpyrimidinyl, hydroxymethylmorpholinyl- pyrimidinyl, carboxymorpho linylpyrimidinyl, (carboxy)(methyl)morpho linylpyrimidinyl, carboxymethylmorpho linylpyrimidinyl, thiomorpholinylpyrimidinyl, oxo- thiomorpholinylpyrimidinyl, dioxo-thiomorpho
  • morpholinylethylpyrazolyl isopropylmethylpyrazolyl, carboxy-3 - azabicyclo[3.1.0]hexanylpyridinyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl, carboxy-3 -azabicyclo [3.1.0]hexanylpyrimidinyl, (carboxy)(methyl)-3 - azabicyclo[3.1.0]hexanylpyrimidinyl, methoxycarbonyl-3 - azabicyclo[3.1.0]hexanylpyrimidinyl, ethoxycarbonyl-3 -azabicyclo [3.1.OJhexanyl- pyrimidinyl, 2-oxa-5-azabicyclo[2.2.1 Jheptanylpyrimidinyl, carboxy-2-oxa-5-azabicyclo- [2.2.1 Jheptanylpyrimidinyl, carboxy-3 -azabicyclo [3.1.1 Jheptanylpyrimi
  • R 1 Additional values of R 1 include difluorocyclobutanyl-pyrimidinyl, difluoromethyl-pyrimidinyl, cyclopropyl-pyrimidinyl, aminoisopropyl-pyrimidinyl,(hydroxy)cyclopropyl-pyrimidinyl, (difluoro)(hydroxy)cyclobutyl-pyrimidinyl, ((methyl)cyclobutane-diol)-pyrimidinyl, (hydroxy)(methyl)cyclohexyl-pyrimidinyl, ((methyl)cyclohexane-diol)-pyrimidinyl, (chloro)(methoxy)pyridinyl, methylsulphinyl-phenyl, cyclopropylsulphonyl-phenyl, tert- butoxy-pyridinyl, methylsulphoximinylpyridinyl, piperazinyl-2-one-pyrimidinyl, (methyl)pyridine
  • R 1 Appropriate values of R 1 include bromo, cyano, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, (di-(trifluoromethyl))(hydroxy)phenyl, chloropyridinyl, tetrahydropyranylpyridinyl, hydroxyisopropylpyridinyl, hydroxymethylpyridinyl, methoxypyridinyl, isopropoxypyridinyl, isopropylpyrimidinyl,
  • piperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, tert- butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl,
  • R 1 Illustrative values of R 1 include bromo, cyano, (methylsulphonyl)methylphenyl, (methylsulphonyl)ethylphenyl, (di-(trifluoromethyl))(hydroxy)phenyl, chloropyridinyl, tetrahydropyranylpyridinyl, hydroxyisopropylpyridinyl, hydroxymethylpyridinyl, methoxypyridinyl, isopropoxypyridinyl, isopropylpyrimidinyl,
  • piperazinylpyrimidinyl carboxypiperazinylpyrimidinyl, tert- butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl,
  • Typical examples of optional substituents on R 2 include C 2 _ 6 alkoxycarbonyl.
  • Typical examples of particular substituents on R 2 include ethoxycarbonyl.
  • R 2 represents hydrogen. In a second embodiment, R 2 represents halogen. In one aspect of that embodiment, R 2 represents fluoro. In another aspect of that embodiment, R 2 represents chloro. In a third embodiment, R 2 represents trifluoromethyl. In a fourth embodiment, R 2 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 2 represents unsubstituted methyl. In another aspect of that embodiment, R 2 represents unsubstituted ethyl. In a further aspect of that embodiment, R 2 represents monosubstituted methyl or monosubstituted ethyl. In a fifth embodiment R 2 represents cyano.
  • Typical values of R 2 include hydrogen, fluoro, chloro, trifluoromethyl, methyl and ethoxycarbony lethy 1.
  • R 2 include hydrogen and fluoro.
  • Z represents an oxygen atom.
  • Z represents a sulphur atom.
  • Z represents -S(O).
  • Z represents -N(R d ).
  • X represents -NH. - -
  • Z represents an optionally substituted straight or branched Ci_4 alkylene chain.
  • Typical values of Z according to this embodiment include methylene (-CH 2 -), (methyl)methylene, ethylene (-CH 2 CH 2 -), (ethyl)methylene, (dimethyl)- methylene, (methyl)ethylene, propylene (-CH 2 CH 2 CH 2 -), (propyl)methylene and (dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents.
  • Z represents an unsubstituted straight or branched Ci_ 4 alkylene chain.
  • Z represents a monosubstituted straight or branched Ci_ 4 alkylene chain.
  • Z represents a disubstituted straight or branched Ci_ 4 alkylene chain.
  • Z represents an unsubtituted methylene.
  • Examples of typical substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, hydroxy, oxo, Ci_ 6 alkoxy, aryl, -C(0)R d , -C0 2 R d , -CONR b R c -S(0)(N-R d )R a , or -S0 2 NR b R c .
  • Z particularly values include methylene, -S(O), oxygen and sulphur.
  • Z is methylene.
  • R 5a represents hydrogen, hydroxy, halogen, trifluoromethyl; -NR b R c , S(0) 2 R a , -OR a , 0-(CO)_R d or -NR c C(0)R d ; or Ci_ 6 alkyl any of which groups may be optionally substituted.
  • R 5a represents hydrogen, hydroxy, halogen, or trifluoromethyl; or - NR b R c , S(0) 2 R a , -OR a , or 0-(CO)_R d ; or Ci_ 6 alkyl any of which groups may be optionally substituted.
  • Suitable examples of optional substituents on R 5a include one, two or three substituents independently selected from halogen, hydroxy, trifluoromethyl, Ci_ 6 alkyl, Ci_ 6 alkoxy , C 2 _ 6 alkylcarbonyl, C 2 _ 6 alkyloxycarbonyl, (hydroxy)Ci_ 6 alkyl , (C3_7)cycloalkyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, di(Ci_6)alkylaminocarbonyl, oxo, and carboxy.
  • substituents on R 5a include one, two or three substituents independently selected from fluoro, chloro, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl, ethyl, isopropyl, isopropylmethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoro-ethoxy, carboxycyclobutyloxy, methylthio, methylsulphonyl, - -
  • aminoisopropyl methylamino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N- (methyl)amino, acetylaminomethyl, methylsulphonylamino, N-methyl-N- (methylsulphonyl) amino, bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino, carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,
  • ethoxycarbonyl n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl, ethoxycarbonyl- methylidenyl, methylsulphonylaminocarbonyl, acetylaminosulphonyl, methoxyamino- carbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl, amino- sulphonyl, methylsulphoximinyl and (methyl)(N-methyl)sulphoximinyl.
  • R 5a represents hydrogen. In a second embodiment, R 5a represents hydroxy. In a third embodiment, R 5a represents halogen. In one aspect of this embodiment, R 5a represents fluoro. In a fourth embodiment, R 5a represents
  • R 5a represents -NR b R c . In one aspect of that embodiment, R 5a represents -NH 2 . In a sixth embodiment, R 5a represents -NR c C(0)R d . In a seventh embodiment, R 5a represents -C(0)-NR c R d . In an eighth embodiment, R 5a represents -NHS(0) 2 R e . In a ninth embodiment, R 5a represents -S-R a . In a tenth embodiment, R 5a represents -S(0)-Ra. In an eleventh embodiment, R 5a represents - S(0) 2 R a . In a particular aspect of this embodiment, R 5a represents -S(0) 2 -CH 3 .
  • R 5a represents -S(0)(N-R d )R a .
  • R 5a represents -S(0) 2 (N-R d ).
  • R 5a represents -OR a .
  • R a is a Ci_ 6 alkyl.
  • R a is an aryl.
  • R a is an heteroaryl.
  • R 5a represents -0-(CO)-R d .
  • R 5a represents -O- (CO)-CH 3 .
  • -C(0)-OR d .
  • R 5a represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 5a represents substituted Ci_ 6 alkyl. In a second aspect of this embodiment, R 5a represents unsubtituted Ci_ 6 alkyl. In a particular aspect of this embodiment, R 5a represents methyl. In an eighteenth embodiment, R 5a represents an optionally substituted C 2 - 6 alkynyl. In a nineteenth embodiment, R 5a represents an optionally substituted heteroaryl.
  • R 5a represents an optionally substituted aryl.
  • R 5a represents an optionally substituted C 2 - 6 alkenyl. - -
  • R 5a represents cyano
  • R 5b represents hydrogen, hydroxy; or optionally substituted C i_ 6 alkyl.
  • Ci_6 alkoxy any of which groups may be optionally substituted.
  • R 5b represents hydrogen. In a second embodiment, R 5b represents hydroxy. In a third embodiment, R 5b represents halogen. In one aspect of this embodiment, R 5a represents fluoro. In a fourth embodiment, R 5b represents
  • R 5b represents substituted or unsubstituted Ci_ 6 alkyl. In one aspect of that embodiment R 5b is methyl. In a sixth embodiment, R 5b represents cyano. Particular values of R 5b include hydrogen and methyl.
  • R 5a and R 5b when taken together with the carbon to which they are attached represent a carbonyl.
  • R 5a and R 5b when taken together with the carbon to which they are attached represent a thiocarbonyl.
  • Illustrative values of R 5a include hydrogen, hydroxy, fluoro, trifluoromethyl, - N(CH 3 ) 2 , -NH(CO)CH 3 , -S0 2 -CH 3 , -0-(CO)-CH 3 , methyl, methoxy, pyridinemethyloxy- , benzyloxy, (methoxycarbonyl)methyloxy-, (ethyloxycarbonyl)methyloxy-, (tert- butoxycarbonyl)methyloxy-, (hydroxycarbonyl)methyloxy and cyanomethyloxy.
  • Selected values of R 5a include hydrogen, hydroxy, fluoro, trifluoromethyl, - N(CH 3 ) 2 , -NH(CO)CH 3 , -S0 2 -CH 3 , -C0 2 -CH 3 , methyl and methoxy.
  • R 5b include hydrogen, hydroxy, fluoro, trifluoromethyl and methyl.
  • R 5a is as defined above and R 5b represents hydrogen.
  • R 5a is hydroxy
  • R 5a is as defined above and R 5b represents Ci_ 4 alkyl, preferably methyl. In a particular aspect of this embodiment, R 5a is hydroxy. - -
  • a particular sub-group of the compounds of formula (IIA) above is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • V represents C-R 12 or N
  • R 9 represents hydrogen, halogen, halo(Ci_6)alkyl, cyano, cyano(Ci_6)alkyl, nitro(Ci_ 6 )alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkoxy, trifluoroethoxy, carboxy(C 3 - 7 )cycloalkyloxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, amino-(Ci_6)alkyl, Ci_ 6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Chalky 1]-N- [hydroxy(C i _ 6 )
  • alkylsulphonylamino N- [(C i _ 6 )alky 1] -N- [(C i _ 6 )alkylsulphonyl] amino, bis [(C i _ 6 )alkyl- sulphonyl] amino, N- [(C i _ 6 )alkyl] -N- [carboxy(C i _ 6 )alkyl] amino, carboxy(C 3 _ 7 )cy cloalkyl- amino, carboxy(C 3 _ 7 )cycloalkyl(Ci_6)alkylamino, formyl, C 2 _ 6 alkylcarbonyl, (C 2 _ 6 )alkyl- carbonyloxy(Ci_6)alkyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6
  • R 9 represents (C 3 - 7 )cycloalkyl, (C 3 _ 7 )cycloalkyl(Ci_6)alkyl, (C4_ 7 )cycloalkenyl, (C4_9)bicycloalkyl, (C 4 _ 9)bicycloalkylene, (C 3 _ 7 )heterocycloalkyl, (C 3 - 7 )heterocycloalkyl(Ci_6)alkyl, (C 3 -
  • R 9 represents Ci_ 6 alkylsulphinyl, (C 3 _ 7 )cycloalkylsulphonyl or difluoromethyl.
  • R 10 and R 1 1 independently represents hydrogen, halogen, cyano, trifluoromethyl, hydroxy; or -NR b R c , -OR a ; Ci_ 6 alkyl, or Ci_ 6 alkylsulphonyl.
  • R 12 represents hydrogen, halogen or Ci_ 6 alkyl
  • Z, Y, R 2 , R 5a and R 5b are as defined above.
  • V represents C-R 12 . In another embodiment, V represents N.
  • R 9 represents hydrogen, halogen, halo(Ci_6)alkyl, cyano, Ci_ 6 alkyl, trifluoromethyl, C 2 _ 6 alkenyl, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy, trifluoroethoxy, carboxy(C 3 -7)cycloalkyloxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_ 6 )alkyl, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N-[(Ci_ 6 )alkyl] -N- [hydro xy(C i _ 6 )alkyl] -amino, N- [(C i _ 6 )alkyl] -N- [carboxy(C i _ _
  • alkylsulphonylamino (C 2 _6)alkylcarbonyl-oxy(Ci_6)alkyl, carboxy, morpholinyl(Ci_
  • R 9 represents (C 3 -7)cycloalkyl, (C 3 -7)cycloalkyl-(Ci_6)alkyl, (C 4 _
  • R 9 represents, amino sulphonyl, Ci_ 6 alkylsulphinyl, (C 3 -7)cycloalkylsulphonyl or difluoromethyl.
  • R 9 represents halogen, hydroxy(Ci_6)alkyl, Ci_ 6 alkylsulphonyl, (Ci_
  • R 9 represents (C 3 _7)cycloalkyl, (C 4 _7)cycloalkenyl, (C 4 _9)bicycloalkyl, (C 3 _7)heterocycloalkyl, (C 4 _9)heterobicycloalkyl or (C 4 _9)bicycloalkylene, any of which groups may be optionally substituted by one or more substituents; or R 9 represents Ci_ 6 alkoxy, aminosulphonyl, Ci_ 6 alkylsulphinyl, (C 3 -
  • R 9 represents halogen, hydroxy(Ci_
  • R 9 represents (C 3 _7)cycloalkyl, (C 4 _7)cycloalkenyl, (C 4 _9)bicycloalkyl, (C 3 -
  • R 9 represents an optionally substituted (C 3 _7)cycloalkyl group
  • typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, any of which groups may be optionally substituted by one or more substituents.
  • R 9 represents an optionally substituted (C 3 -7)cycloalkyl(Ci_6)alkyl group
  • a typical value is cyclohexylmethyl, which group may be optionally substituted by one or more substituents.
  • R 9 represents an optionally substituted (C4_7)cycloalkenyl group
  • typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, any of which groups may be optionally substituted by one or more substituents.
  • R 9 represents an optionally substituted (C4_9)bicycloalkyl group
  • typical values include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl, any of which groups may be optionally substituted by one or more substituents.
  • R 9 represents an optionally substituted (C4_9)bicycloalkenyl group
  • a typical value is bicyclo[3.1.0]hexenyl.
  • R 9 represents an optionally substituted (C3_7)heterocycloalkyl group
  • typical values include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydro-pyranyl, piperidinyl, piperazinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl,
  • R 9 represents an optionally substituted (C3_7)heterocycloalkenyl group, a typical value is optionally substituted 1 ,2,3,6-tetrahydropyridinyl or 3,6-dihydropyridine.
  • R 9 represents an optionally substituted (C4_9)heterobicycloalkyl group
  • typical values include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3- azabicyclo[3.1.l]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo- [3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6- diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1 Jnonanyl, 3,9-diazabicyclo- [4.2.1
  • R 9 represents an optionally substituted (C4-9)spiroheterocycloalkyl group
  • typical values include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl, 2-azaspiro[3.3]- heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro- [3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl and 2,4,8-triazaspiro[4.5]-decanyl, any of which groups may be optionally substituted by one or more substituents.
  • R 9 represents an optionally substituted heteroaryl
  • typical values include triazolyl and (methyl)triazolyl.
  • R 9 represents a Ci_ 6 alkylsulphinyl
  • typical values include methylsulphinyl.
  • R 9 represents (C3_7)cycloalkylsulphonyl
  • typical values include
  • R 9 represents hydrogen, isopropyl, isopropylmethyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, carboxy-cyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylmethyl, methylamino, N-[carboxy ethyl] -N-methyl- amino, carboxycyclopentylamino, carboxycyclopropylmethylamino or ethoxycarbonyl- ethyl; or R 9 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl- methyl, cyclohexenyl, bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl
  • R 9 represents hydrogen, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, tetrahydropyranyl, thiopyranyl, piperazinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl,
  • R 9 represents difluoromethyl, hydroxyisopropyl, fluoroisopropyl, aminoisopropyl, aminosulphonyl, tert-butoxy, methylsulphonyl,
  • R 9 represents hydrogen, cyclopropyl, cyclobutyl,
  • R 9 examples include one, two or three substituents independently selected from halogen, halo(Ci_6)alkyl, cyano, cyano- (Ci_6)alkyl, nitro, nitro (Chalky 1, Ci_ 6 alkyl, C 3 -7 cycloalkyl, trifluoromethyl,
  • R 9 Selected examples of optional substituents on R 9 include one, two or three substituents independently selected from halogen, cyano, trifluoromethyl, hydroxy, Ci_ 6 alkyl, C 3 -7 cycloalkyl,Ci_6 alkoxy, Ci_ 6 alkylsulphonyl, Ci_ 6 alkylsulphoximinyl, Ci_ 6 alkylcarbonyl, Ci_ 6 alkoxycarbonyl oxo and carboxy.
  • Suitable examples of particular substituents on R 9 include one, two or three substituents independently selected from fluoro, fluoromethyl, chloro, bromo, cyano, cyanomethyl, cyanoethyl, nitro, nitromethyl, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, hydroxymethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoro ethoxy, methylthio, methylsulphonyl, methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, methylamino, dimethylamino, acetylamino, acetyl-aminomethyl, methoxy carbonylamino, ethoxycarbonylamino, tert- butoxycarbonylamino, methylsulphony
  • Selected examples of particular substituents on R 9 include one, two or three substituents independently selected chloro, hydroxy, methyl, isopropyl, trifluoromethyl, tert-butoxycarbonyl, acetyl, oxo and carboxy. Additional example of particular substituent on R 9 include fluoro.
  • R 9 represents hydrogen, fluoro, fluoroisopropyl, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoro-ethoxy, carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylmethyl, amino, methylamino, dimethylamino, methoxy ethylamino, N- (hydroxyethyl)-N-(methyl)amino, N-[carboxy-ethyl]-N-methylamino,
  • carboxycyclopentylamino carboxy cyclopropylmethylamino, methylsulphonylamino, acetoxyisopropyl, carboxy, ethoxycarbonylethyl, cyclopropyl , fluoromethyl-cyclopropyl, acetylaminomethylcyclopropyl, hydroxycyclo butyl, carboxycyclopentyl,
  • piperidinyl (amino)(carboxy)piperidinyl, carboxymethylpiperidinyl, methoxycarbonyl- piperidinyl, (methoxycarbonyl)(methyl)piperidinyl, (ethyl)(methoxycarbonyl)piperidinyl, (isopropyl)(methoxycarbonyl)piperidinyl, (methoxy)(methoxycarbonyl)piperidinyl, (carboxy)(methoxycarbonyl)piperidinyl, ethoxycarbonylpiperidinyl, (ethoxycarbonyl)- (fluoro)piperidinyl, (ethoxycarbonyl)(methyl)piperidinyl, (ethoxycarbonyl)(trifluoro- methyl)piperidinyl, (ethoxycarbonyl)(hydroxymethyl)piperidinyl, (n-butoxycarbonyl)- (methyl)piperidinyl, (methyl)(morph
  • cyanoethylpiperazinyl trifluoroethyl-piperazinyl, methylsulphonylpiperazinyl, methylsulphonylethylpiperazinyl, oxopiperazinyl, acetylpiperazinyl, carboxypiperazinyl, tert-butoxycarbonylpiperazinyl, carboxymethylpiperazinyl, carboxyethylpiperazinyl, ethoxycarbonylmethylpiperazinyl, ethoxycarbonylethylpiperazinyl,
  • tetrazolylmethylpiperazinyl trioxohexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl, dimethylmorpholinyl, hydroxymethyl-morpholinyl, carboxymorpholinyl, (carboxy)(methyl)morpholinyl, carboxymethyl-morpho linyl, thio morpholinyl,
  • oxothiomorpholinyl dioxothiomorpholinyl, carboxy-azepanyl, carboxyoxazepanyl, oxodiazepanyl, (methyl)(oxo)diazepanyl, dioxo-thiadiazepanyl, carboxy-3- azabicyclo[3.1.0]hexanyl, (carboxy)(methyl)-3-azabicyclo-[3.1.0]hexanyl,
  • R 9 represents difluorocyclobutanyl, difluoromethyl, tert- butoxy, amino isopropyl, hydroxycyclopropyl, (difluoro)(hydroxy)cyclobutyl,
  • R 9 include chloro, tetrahydropyranyl, hydroxyisopropyl, hydroxymethyl, methoxy, isopropoxy, isopropyl, hydroxycyclobutyl,
  • R 9 methylsulphinyl, methylsulphoximinyl, cyclopropylsulphonyl, .2,5- diazabicyclo[2.2.1 Jhetanyl and methylcarboxy-3-azabicyclo[3.2.1 Joctanyl.Illustrative values of R 9 include chloro, tetrahydropyranyl, hydroxyisopropyl, hydroxymethyl, methoxy, isopropoxy, isopropyl, hydroxycyclobutyl, carboxybicyclo[3.1.0]hexanyl, carboxybicyclo[3.1.0]hexenyl, piperazinyl, hydroxyoxetanyl, hydroxyazetidinyl,
  • R 10 represents hydrogen. In a second embodiment, R 10 represents halogen. In a third embodiment, R 10 represents cyano. In a fourth embodiment, R 10 represents trifluoromethyl. In a fifth embodiment, R 10 represents hydroxy. In a sixth embodiment, R 10 represents -NR b R c . In one aspect of this embodiment R 10 represents - NH 2 . In a seventh embodiment, R 10 represents -OR a . In one aspect of that embodiment, R 10 represents methoxy. In an eighth embodiment, R 10 represents Ci_ 6 alkyl. In one aspect of that embodiment, R 10 represents methyl. In a ninth embodiment, R 10 represents Ci_ 6 alkylsulphonyl.
  • R 10 represents methylsulphonyl.
  • R 1 1 represents hydrogen.
  • R 11 represents halogen.
  • R 1 1 represents cyano.
  • R 1 1 represents trifluormethyl.
  • R 1 1 represents hydroxy.
  • R 1 1 represents -NR b R c .
  • R 1 1 represents - NH 2 .
  • R 1 1 represents -OR a .
  • R 1 1 represents methoxy.
  • R 1 1 1 represents Ci_ 6 alkyl.
  • R 11 represents methyl.
  • R 1 1 1 represents Ci_ 6 alkylsulphonyl.
  • R 1 1 1 represents methylsulphonyl.
  • R 10 and R 1 1 include hydrogen, methyl and methylsulphonyl.
  • Particular sub-groups of the compounds of formula (IIB) above are represented by the compounds of formula (IIC), (IID), (HE), (IIF), (IIG) , (IIH), (IIJ), (IIK), (IIL), (IIM) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • T represents -CH 2 - or -CH 2 CH 2;
  • U represents C(O) or S(0) 2 ;
  • W represents O, S, S(O), S(0) 2 , N(R 14 ), S(0)(N-R d ) or C(R 15 )(R 16 );
  • -M- represents -CH 2 -, -CH 2 CH 2 -or -CH 2 -W-CH 2 -;
  • Q represents C(R 15 )(R 16 );
  • R 13 represents hydrogen, halogen, cyano, halo(Ci_6)alkyl, hydroxy, Ci_ 6 alkoxy, Ci_6 alkylthio, Ci_ 6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, amino, Ci_ 6 alkylamino, di(Ci_ 6 )alkyl-amino, (C 2 _6)alkylcarbonylamino, (C 2 _6)alkylcarbonylamino(Ci_6)alkyl, (Ci_6)alkyl- sulphonylamino or (Ci_6)alkylsulphonylamino(Ci_6)alkyl;
  • R 14 represents hydrogen, cyano(Ci_6)alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoro- ethyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, a carboxylic acid isostere or prodrug moiety ⁇ as defined herein,
  • aminocarbonyl Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl or di(Ci_6)alkylamino-sulphonyl;
  • R 15 represents hydrogen, halogen, cyano, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkylsulphonyl, formyl, C 2 _ 6 alkylcarbonyl, di(Ci_ 6 alkyl)aminocarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, aminosulphonyl, (Ci_6)alkyl-sulphoximinyl, [(Ci_6)alkyl][N-(Ci_6)alkyl]sulphoximinyl, a carboxylic acid isostere or prodrug moiety ⁇ as defined herein, or
  • R 16 represents hydrogen, halogen, Ci_ 6 alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, hydroxy-(Ci_6)alkyl, Ci_ 6 alkoxy, amino or carboxy; and V, Y, Z, R 2 , R 5a , R 5b , R 10 and R 1 1 are as defined above.
  • T represents -CH 2 -. In a second embodiment T represents - CH 2 CH 2;
  • U represents C(O). In another embodiment, U represents
  • W represents O, S(0) 2 , S(0)(N-R d ), N(R 14 ) or C(R 15 )(R 16 ).
  • W represents O, N(R 14 ) or C(R 15 )(R 16 ).
  • W represents O. In a second embodiment, W represents S. In a third embodiment, W represents S(O). In a fourth embodiment, W represents S(0) 2 . In a fifth embodiment, W represents N(R 14 ). In a particular aspect of this embodiment, W represents -NH. In a sixth embodiment, W represents C(R 15 )(R 16 ). In a seventh embodiment,
  • W represents S(0)(N-R d ). In a particular aspect of that embodiment, W represents S(0)(NH).
  • -M- represents -CH 2 -. In a second embodiment, -M- represents -CH 2 CH 2 -. In a third embodiment M represents CH 2 -W-CH 2 . In one aspect of that embodiment, M represents CH 2 -0-CH 2 . In a second aspect of that embodiment, M represents CH 2 -S(0)(N-R d )-CH 2 . In a third aspect of that embodiment, M represents CH 2 - S-CH 2 . In a fourth aspect of that embodiment, M represents CH 2 -S(0)-CH 2 . In a fifth aspect of that embodiment, M represents CH 2 -S(0) 2 -CH 2 . In a sixth aspect of that embodiment, M represents CH 2 -N(R 14 )-CH 2 . In a seventh aspect of that embodiment, M represents CH 2 - C(R 15 )(R 16 )-CH 2 .
  • R 13 represents hydrogen. In a second embodiment, R 13 represents halogen. In one aspect of that embodiment, R 13 represents fluoro. In a third embodiment, R 13 represents halo(Ci_6)alkyl. In one aspect of that embodiment, R 13 represents fluoromethyl. In another aspect of that embodiment R 13 represents
  • R 13 represents hydroxy.
  • R 13 represents Ci_ 6 alkoxy. In a particular aspect of that embodiment, R 13 represents methoxy.
  • R 13 represents Ci_ 6 alkylthio. In a particular aspect of that embodiment, R 13 represents methylthio.
  • R 13 represents Ci_ 6 alkylsulphinyl. In a particular aspect of that embodiment, R 13 represents methylsulphinyl.
  • R 13 represents Ci_ 6 alkylsulphonyl. In a particular aspect of that embodiment, R 13 represents methylsulphonyl.
  • R 13 represents amino.
  • R 13 represents Ci_ 6 alkylamino. In a particular aspect of that embodiment, R 13 represents methylamino. In an eleventh embodiment, R 13 represents di(Ci_6)alkylamino. In a particular aspect of that embodiment, R 13 represents
  • R 13 represents (C 2 _6)alkylcarbonylamino. In a particular aspect of that embodiment, R 13 represents acetylamino. In a thirteenth - -
  • R 13 represents (C 2 -6)alkylcarbonylamino(Ci_6)alkyl. In a particular aspect of that embodiment, R 13 represents acetylaminomethyl. In a fourteenth embodiment, R 13 represents (Ci_6)alkylsulphonyl-amino. In a particular aspect of that embodiment, R 13 represents methylsulphonylamino. In a fifteenth embodiment, R 13 represents (Ci_ 6)alkylsulphonylamino(Ci_6)alkyl. In a particular aspect of that embodiment, R 13 represents methylsulphonylaminomethyl. In a sixteenth embodiment, R 13 represents cyano.
  • R 13 represents hydrogen, halogen, halo(Ci_6)alkyl, hydroxy or
  • Selected values of R 13 include hydrogen, fluoro, fluoromethyl, hydroxy, methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino, methylamino, dimethylamino and acetylaminomethyl.
  • R 13 include hydrogen, fluoro, fluoromethyl, hydroxy and acetylaminomethyl.
  • R 13 represents hydrogen, hydroxy or fluoro.
  • R 14 represents hydrogen, cyano(Ci_6)alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoroethyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C 2 - 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 - 6 alkoxycarbonyl, C 2 - 6 alkoxycarbonyl- (Ci_6)alkyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl, Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkyl- aminocarbonyl, aminosulphonyl, Ci_ 6 alky lamino sulphonyl or di(Ci_6)alkylamino- sulphonyl.
  • R 14 represents hydrogen, Ci_ 6 alkyl or C 2 - 6 alkylcarbonyl.
  • Typical values of R 14 include hydrogen, cyanoethyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl, methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolylmethyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylamino sulphonyl.
  • R 14 include hydrogen, methyl and acetyl.
  • R 14 represents hydrogen. In a selected embodiment, R 14 represents Ci_ 6 alkyl. - -
  • R 14 represents C 2 _ 6 alkylcarbonyl.
  • R 15 represents halogen, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6
  • alkoxycarbonyl di(Ci_ 6 alkyl)aminocarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, a carboxylic acid isostere or prodrug moiety ⁇ as defined herein, or
  • R 15 represents hydrogen, halogen, cyano, hydroxy, hydroxy(Ci_6)alkyl, Ci_6 alkylsulphonyl, formyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, aminosulphonyl, (Ci_6)alkylsulphoximinyl, [(Ci_ 6 )alkyl][N- (C i _6)alkyl] sulphoximinyl, (C i _6)alkylsulphonylaminocarbonyl, (C 2 _6)alkylcarbonylamino- sulphonyl, (Ci_6)alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl.
  • Typical values of R 15 include hydrogen, fluoro, cyano, hydroxy, hydroxymethyl, methylsulphonyl, formyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, aminosulphonyl, methylsulphoximinyl, (methyl)(N-methyl)sulphoximinyl, methylsulphonylaminocarbonyl,
  • R 15 represents carboxy
  • R 16 represents hydrogen, halogen, C3-7 cyloalkyl or Ci_ 6 alkyl.
  • R 16 represents hydrogen or Ci_ 6 alkyl.
  • Selected values of R 16 include hydrogen, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, amino and carboxy.
  • R include hydrogen and methyl.
  • R represents hydrogen
  • R 16 represents halogen. In one aspect of that
  • R 16 represents fluoro. In a third embodiment, R 16 represents Ci_ 6 alkyl. In a first aspect of that embodiment, R 16 represents methyl. In a second aspect of that embodiment, R 16 represents ethyl. In a third aspect of that embodiment, R 16 represents isopropyl. In a fourth embodiment, R 16 represents trifluoromethyl. In a fifth embodiment, R 16 represents hydroxy. In a sixth embodiment, R 16 represents hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 16 represents hydroxymethyl. In a seventh embodiment, R 16 - -
  • R 16 represents Ci_ 6 alkoxy. In one aspect of that embodiment, R 16 represents methoxy. In an eighth embodiment, R 16 represents amino. In a ninth embodiment, R 16 represents carboxy. In a tenth embodiment, R 16 represents a C 3 _ 7 cycloalkyl. In one aspect of this embodiment, R 16 represents cyclopropyl.
  • An alternative sub-class of compounds according to the invention is represented by the compounds of formula (IIN) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • R 2 , R 5a , R 5b , R 9 , R 10 and R 11 are as defined above.
  • Z represents methylene
  • Y represents 2- difluromethoxy-phenyl. In another particular embodiment of compounds of formula (IIN), Y represents 2-difluromethoxy-5-chloro-phenyl.
  • R 2 represents hydrogen. In a particular embodiment of compounds of formula (IIN), R 2 represents flurorine.
  • R 5a represents hydroxy
  • R 5b represents hydrogen
  • R 9 represents Ci_ 4 alkylsulphonyl. In a particular aspect of that embodiment, R 9 represents methyl sulphonyl. In another particular embodiment of compounds of compounds of formula (IIN), R 9 represents C 3 _ 7 cycloaklysulphonyl. In a particular aspect of this embodiment, R 9 represents cyclopropyl sulphonyl. In a further particular embodiment of compound of - -
  • R 9 represents aminosulphonyl. In another further particular embodiment of compound of formula (UN), R 9 represents methylsulphoximinyl.
  • R 10 represents hydrogen.
  • R 11 represents hydrogen.
  • An alternative sub-class of compounds according to the invention is represented by the compounds of formula (IIP) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • W, Z, R 2 , R 5a , R 5b and R 9 are as defined above.
  • novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof, and co-crystals thereof.
  • the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders.
  • Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, polymyositis, scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof), anaemia of chronic disease (ACD), Still's disease (juvenile and/or adult onset), Beliefs disease and Sjogren's syndrome.
  • Organ-specific autoimmune disorders include Addison's disease, haemo lytic or pernicious anaemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune card
  • Neurological and neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.
  • Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders (including erectile dysfunction and female sexual dysfunction).
  • Modulators of TNFa function may also be of use in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).
  • Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.
  • Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularisation (including corneal vascularisation and neovascularisation), retinal vein occlusion, and various forms of uveitis and keratitis.
  • retinopathy including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity
  • macular oedema including diabetic macular oedema
  • vascularisation including corneal vascularisation and neovascularisation
  • retinal vein occlusion and various forms of uveitis and keratitis.
  • Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal - -
  • haematological malignancy including leukaemia and lymphoma
  • non-haematological malignancy including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma.
  • Chronic leukaemia may be myeloid or lymphoid.
  • leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplasia syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythro leukaemia.
  • CML chronic myelogenous leukaemia
  • CLL chronic lymphocytic/lymphoid leukaemia
  • ALL acute lymphoblastic leukaemia
  • AML acute myelogenous leukaemia
  • lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma.
  • non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
  • Modulators of TNFa function may also be used to increase the safety of the potent anticancer effect of TNF (see F.V.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, micro crystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulfate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, micro crystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glyco
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration. - -
  • the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
  • the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • a compound in accordance with the present invention may be co- administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.
  • another pharmaceutically active agent e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV), to afford a compound of formula (VI):
  • L 1 represents a suitable leaving group.
  • E represents -CH 2 -Y or hydrogen.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a Ci_ 4 alkanol such as ethanol, or an ether such as 1,4-dioxane or dimethoxyethane, and in the presence of magnesium sulphate.
  • a suitable solvent e.g. a Ci_ 4 alkanol such as ethanol, or an ether such as 1,4-dioxane or dimethoxyethane
  • intermediates of formula (V), as defined here above may be prepared according to a process which comprises reacting an intermediate of formula (VII) wherein; R d , R 1 , R 2 , R 3 and R 4 are as defined above, with a compound of formula H-
  • reaction is conveniently effected in a suitable solvent e.g. acetonitrile, in the the presence of L-proline and magnesium sulphate, at elevated temperature, e.g. 80°C.
  • a suitable solvent e.g. acetonitrile
  • L-proline and magnesium sulphate at elevated temperature, e.g. 80°C.
  • Intermediates of formula (VII), wherein R 1 is halogen may be prepared from intermediates of formula (VIII) wherein R 1 , R 2 , R 3 and R 4 are as defined for intermediate of formula (VII) above, by reaction with intermediate of formula (IX) wherein, L 1 and R d are as defined for intermediate (IV) above.
  • reaction conditions are analogous to the ones used here above for the reaction between intermediate (III) and intermediate (IV).
  • Compound of formula (V) wherein E is hydrogen i.e. intermediate (VII)
  • This reaction is conveniently performed at elevated temperature in a suitable solvent, e.g. dimethylformamide.
  • Compound of formula (V) wherein E is -(CO)-H may be transformed into compound of formula (V) wherein E is -CH(OH)-Y , for example by treatment with Y- MgX in a suitable solvent, e.g. THF.
  • a suitable solvent e.g. THF.
  • X is halogen, e.g. bromo or chloro.
  • Compound of formula (V) wherein E is -CH(OH)-Y may be transformed, for example into compound of formula (V) wherein E is -CH(C1)-Y by reaction with sulfonylchloride in a suitable solvent e.g. dichloromethane.
  • Compound of formula (V) wherein E is -CH(C1)-Y may be transformed into compound of formula (VI), wherein wherein Y, Q 1 , R d , R 1 , R 2 , R 3 and R 4 are as defined above, for example in a three step reaction including (i) reaction with Q 1 -CH 2 -L 2 wherein Q 1 is, for example, an C 2 _ 6 alkoxycarbonyl and L 2 is a suitable leaving group, e.g. C 2 _ 6 alkoxycarbonyl, in the presence of a base, e.g. sodium hydride, in a suitable solvent e.g. THF, (ii) decarbalkoxylation by treatment with an acid, e.g. HC1, at elevated temperature - -
  • (VII) may be transformed into compound of formula (V) wherein E is a halogen, e.g. iodo or bromo, for example, by treatement with the corresponding N-halo-succinimide, N- Bromo or N-iodo -succinimide in the presence of an acid, e.g. acetic acid.
  • E is a halogen, e.g. iodo or bromo, for example, by treatement with the corresponding N-halo-succinimide, N- Bromo or N-iodo -succinimide in the presence of an acid, e.g. acetic acid.
  • Compound of formula (V) wherein E is halogen may be further transformed into compound of formula (V) wherein E is -CH(OH)-Y, by reaction for example with Y- (CO)H in the presence of an alkyl magnesium salt , e.g. isopropylmagnesiumchloride, in a suitable solvent, e.g. THF.
  • an alkyl magnesium salt e.g. isopropylmagnesiumchloride
  • L 3 is typically a halogen, for example bromine.
  • Q 1 is typically methoxycarbonyl or ethylcarbonyl.
  • This reaction is conveniently performed in a suitable solvent, e.g. THF, in the presence of potassium bis(trimethylsilyl)amide.
  • a suitable solvent e.g. THF
  • Compound of formula (VI) may further be cyclized affording compound of formula (I) wherein R 5a and R 5b together with the carbon to which they are attached form a carbonyl and Z is CH-Q 1 and Q 1 is as defined above.
  • a suitable solvent e.g. THF in the presence of a base, e.g. potassium tert-butoxide.
  • Compound of formula (I) wherein Z is CH-Q 1 may be transformed into compound of formula (I) wherein Z is -CH 2 - for example by treatment with an acid, e.g. HC1, at elevated temperature.
  • an acid e.g. HC1
  • a compound of formula (I) which contains a carbonyl group in particular a compound of formula (I) wherein R 5a and R 5b with the carbon atom to which they are attached form a carbonyl, may be transformed into the corresponding compound wherein R 5a is a hydroxy group and R 5b is a hydrogen using for example lithium-tri-sec-butyl- borohydride or sodium borohydride in a suitable solvent e.g. THF.
  • a compound of formula (I) which contains a carbonyl group in particular a compound of formula (I) wherein R 5a and R 5b with the carbon atom to which they are attached form a carbonyl, may be transformed into the corresponding compound wherein R 5a is a trifluoromethyl and R 5b is a hydroxy by treatement with trifluormethylsilane at room temperature in a suitable solvent e.g. dimethoxyethane.
  • a compound of formula (I) which contains a carbonyl group in particular a compound of formula (I) wherein R 5a and R 5b with the carbon atom to which they are attached form a carbonyl, may be transformed into the corresponding compound wherein R 5a is a (Ci_6 alkyl)sulphonylaryloxy trifluoromethyl and R 5b is a hydrogen by treatement with (Ci_6 alkyl)sulphonylphenol, in the presence of Disiopropyl €-1,2- diazenedicarboxylate, in a suitable solvent, e.g THF.
  • a suitable solvent e.g THF.
  • a compound of formula (I) which contains a hydroxy group in particular a compound of formula (I) wherein R 5a is a hydroxy group and R 5b is a hydrogen, may be transformed into corresponding compound wherein R 5a and R 5b are hydrogen for example by treatement with iodotrimethylsilane in a suitable solvent, e.g. acetonitrile.
  • a suitable solvent e.g. acetonitrile
  • a compound of formula (I) which contains a hydroxy group in particular a compound of formula (I) wherein R 5a is a hydroxy group and R 5b is a hydrogen, may be transformed in a two step reaction into corresponding compound wherein R 5a is -NH 2 and R 5b is hydrogen for example by (i) treatment with diphenylphosphorylazide and 1 ,8- diazabicyclo[5.4.0]undec-7-ene. This reaction is conveniently performed at 0°C in THF; (ii) subsequent aza-wittig reaction using PPh 3 in a suitable solvent, e.g. a mixture of water and toluene.
  • a suitable solvent e.g. a mixture of water and toluene.
  • a compound of formula (I) which contains a hydroxy group in particular a compound of formula (I) wherein R 5a is a hydroxy group and R 5b is a hydrogen, may be transformed into corresponding compound wherein R 5a is -F and R 5b is hydrogen by treatement with diethylaminosulfur trifluoride in a suitable solvent, e.g. THF.
  • a suitable solvent e.g. THF.
  • a compound of formula (I) which contains a hydroxy group in particular a compound of formula (I) wherein R 5a is a hydroxy group and R 5b is a hydrogen, may betransformed into the corresponding compound of formula (I) wherein R 5a is a Ci_ 4 alkyl, e.g. methyl, and R 5b is a hydrogen by treatment for example with an alkylmagnesium bromide in a suitable solvent, for example diethylether.
  • a compound of formula (I) which contains a hydroxy group in particular a compound of formula (I) wherein R 5a is a hydroxy group and R 5b is a hydrogen may be transformed into the corresponding compound wherein R 5a is a Ci_ 4 alkoxy, e.g. methoxy, and R 5b is a hydrogen by treatement with a base e.g. sodium hydride, in a suitable solvent, e.g. THF, in the presence of a suitable alkylation agent, such as an alkylhalide, e.g. methyliodide.
  • a base e.g. sodium hydride
  • a suitable solvent e.g. THF
  • a suitable alkylation agent such as an alkylhalide, e.g. methyliodide.
  • a compound of formula (I), wherein R 5a is a hydroxy group may be converted into the corresponding compound of formula (I) wherein R 5a is OR a and R a is an alkyl substituted by an alkoxycarbonyl group, by treatment with a base, e.g. sodium hydride and addition of the corresponding alkoxy carbonylalkylhalide, in a suitable solvent e.g. tetrahydroiuran. It will be apparent that a similar reaction may be performed for the conversion of a compound of formula (I), wherein R 5a is a hydroxy group into the - -
  • a compound of formula (I) which contains a hydroxy group may be alkylated by treatment with the appropriate alkyl halide in the presence of a base, e.g. sodium hydride, or silver oxide.
  • a compound of formula (I) which contains hydroxy may be converted into the corresponding fluoro-substituted compound by treatment with diethylamino sulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (BAST).
  • DAST diethylamino sulfur trifluoride
  • BAST bis(2-methoxyethyl)aminosulfur trifluoride
  • a compound of formula (I) which contains hydroxy may be converted into the corresponding difluoro- substituted compound via a two-step procedure which comprises: (i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii) treatment of the carbonyl-containing compound thereby obtained with DAST.
  • an oxidising agent e.g
  • a compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl halide, typically at an elevated temperature in an organic solvent such as acetonitrile; or at ambient temperature in the presence of a base, e.g. an alkali metal carbonate such as potassium carbonate or cesium carbonate, in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
  • a compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl tosylate in the presence of a base, e.g. an inorganic base such as sodium hydride, or an organic base such as l ,8-diazabicyclo[5.4.0]undec-7- ene (DBU).
  • a compound of formula (I) which contains an N-H moiety may be methylated by treatment with formaldehyde in the presence of a reducing agent, e.g. sodium triacetoxyborohydride.
  • a reducing agent e.g. sodium triacetoxyborohydride.
  • a compound of formula (I) which contains an N-H moiety may be acylated by treatment with the appropriate acid chloride, e.g. acetyl chloride, or with the appropriate carboxylic acid anhydride, e.g. acetic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine.
  • the appropriate acid chloride e.g. acetyl chloride
  • carboxylic acid anhydride e.g. acetic anhydride
  • a compound of formula (I) which contains an N-H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by Ci_ 6 alkyl- sulphonyl, e.g. methylsulphonyl, by treatment with the appropriate Ci_ 6 alkylsulphonyl chloride, e.g. methanesulphonyl chloride, or with the appropriate Ci_ 6 alkylsulphonic acid anhydride, e.g. methanesulphonic anhydride, typically at ambient temperature in the - -
  • a base e.g. an organic base such as triethylamine or N,N-diisopropylethyl- amine.
  • a compound of formula (I) substituted by amino (-NH 2 ) may be converted into the corresponding compound substituted by Ci_ 6 alkylsulphonylamino, e.g. methylsulphonyl- amino, or bis[(Ci_6)alkylsulphonyl]amino, e.g. bis(methylsulphonyl)amino, by treatment with the appropriate Ci_ 6 alkylsulphonyl halide, e.g. a Ci_ 6 alkylsulphonyl chloride such as methanesulphonyl chloride.
  • a compound of formula (I) substituted by hydroxy (-OH) may be converted into the corresponding compound substituted by Ci_ 6 alkyl- sulphonyloxy, e.g. methylsulphonyloxy, by treatment with the appropriate Ci_ 6 alkyl- sulphonyl halide, e.g. a Ci_ 6 alkylsulphonyl chloride such as methanesulphonyl chloride.
  • a compound of formula (I) containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(O)- by treatment with 3-chloroperoxy- benzoic acid.
  • a compound of formula (I) containing the moiety -S(O)- may be converted into the corresponding compound containing the moiety -S(0) 2 - by treatment with 3-chloroperoxybenzoic acid.
  • a compound of formula (I) containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(0) 2 - by treatment with Oxone® (potassium peroxymonosulfate).
  • a compound of formula (I) containing an aromatic nitrogen atom may be converted into the corresponding N-oxide derivative by treatment with 3-chloroperoxy- benzoic acid.
  • a compound of formula (I) which contains a carbonyl may be converted into the corresponding alcohol by treatment with a suitable borohydride, e.g. lithium-tri-sec-butyl- borohydride or sodium borohydride, in a suitable solvent e.g. THF.
  • a suitable borohydride e.g. lithium-tri-sec-butyl- borohydride or sodium borohydride
  • a bromophenyl derivative of formula (I) may be converted into the corresponding optionally substituted 2-oxopyrrolidin-l-ylphenyl or 2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-one or oxazolidin-2-one, or an appropriately substituted analogue thereof.
  • the reaction is conveniently effected at an elevated temperature in the presence of copper(I) iodide, trans-N,N'-dimethylcyclohexane-l ,2- diamine and an inorganic base such as potassium carbonate.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo may be converted into the corresponding compound wherein R 1 represents an optionally substituted aryl or heteroaryl moiety by treatment with the appropriately substituted aryl or - -
  • heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol e.g. pinacol, 1,3-propanediol or neopentyl glycol.
  • the reaction is typically effected in the presence of a transition metal catalyst, e.g. [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), or bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate, or potassium phosphate.
  • This reaction may conveniently be performed in a 1,4-dioxane with or without the use of micro wave technology.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted aryl, heteroaryl or heterocycloalkenyl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately functionalised halo- or tosyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivative.
  • halogen e.g. bromo
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [ ⁇ , -bis- (diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex.
  • a transition metal catalyst such as [ ⁇ , -bis- (diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex.
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as tetrakis- (triphenylphosphine)palladium(O), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 - yljiron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a transition metal catalyst such as tetrakis- (triphenylphosphine)palladium(O), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 - yljiron-dichloropalladium-dichloromethane complex
  • a base e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally an optionally substituted pyridine-2(lH)-one, via a two-step procedure which comprises : (i) reaction with the corresponding optionally substituted 4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)pyridine, in a suitable solvent, e.g. 1,4-dioxane, in the presence of an inorganic base e.g.
  • a suitable solvent e.g. 1,4-dioxane
  • reaction is conveniently effected a a high temperature in a microwave oven.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted C 2 _ 6 alkynyl moiety by treatment with an appropriately substituted alkyne derivative, e.g. 2-hydroxybut-3-yne.
  • the reaction is conveniently accomplished with the - -
  • transition metal catalyst e.g. tetrakis(triphenylphosphine)palladium(0)
  • a base e.g. an organic base such as triethylamine
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted imidazol-l-yl moiety by treatment with the appropriately substituted imidazole derivative, typically in the presence of copper(II) acetate and an organic base such as N,N,N',N'-tetramethy lethy lenediamine (TMED A) .
  • TMED A N,N,N',N'-tetramethy lethy lenediamine
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents 2-(methoxycarbonyl)- ethyl via a two-step procedure which comprises: (i) reaction with methyl acrylate; and (ii) catalytic hydrogenation of the alkenyl derivative thereby obtained, typically by treatment with a hydrogenation catalyst, e.g. palladium on charcoal, under an atmosphere of hydrogen gas.
  • Step (i) is typically effected in the presence of a transition metal catalyst, e.g. palladium(II) acetate or bis(dibenzylideneacetone)palladium(0), and a reagent such as tri(ortAo-tolyl)phosphine.
  • a hydrogenation catalyst e.g. palladium on charcoal
  • a base e.g. an alkali metal hydroxide such as sodium hydroxide.
  • a compound of formula (I) wherein R 1 represents 6-methoxypyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 2-oxo-l,2-dihydro- pyridin-5-yl by treatment with pyridine hydrochloride; or by heating with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 1 represents 6-methoxy-4-methylpyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 4-methyl-2-oxo-l,2-dihydropyridin-5-yl; and a compound of formula (I) wherein R 1 represents 6-methoxy-5-methylpyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 3-methyl-2- oxo-l,2-dihydropyridin-5-yl.
  • a compound of formula (I) wherein R 1 represents 2-oxo-l,2-dihydropyridin-5-yl may be converted into the corresponding compound wherein R 1 represents 2-oxopiperidin- - -
  • a compound of formula (I) wherein R 1 represents 2-methoxy-3-methyl-pyridin-yl may be converted into the corresponding compound wherein R 1 represents 3-methyl- pyridin-2(H)-one by treatment with sodium idodide and boron trifluoride ethyl etherate in acetonitrile.
  • a compound of formula (I) containing an ester moiety e.g. a C 2 _ 6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may be converted into the corresponding compound containing a carboxy (-C0 2 H) moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.
  • an acid e.g. a mineral acid such as hydrochloric acid.
  • a compound of formula (I) containing an N-(tert-butoxycarbonyl) moiety may be converted into the corresponding compound containing an N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • a compound of formula (I) containing an ester moiety e.g. a C 2 _ 6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may alternatively be converted into the corresponding compound containing a carboxy (-C0 2 H) moiety by treatment with a base, e.g.
  • a compound of formula (I) containing a carboxy (-C0 2 H) moiety may be converted into the corresponding compound containing an amide moiety by treatment with the appropriate amine in the presence of a condensing agent such as l-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide.
  • a compound of formula (I) containing a hydroxymethyl moiety may be converted into the corresponding compound containing a formyl (-CHO) moiety by treatment with an oxidising agent such as Dess-Martin periodinane.
  • a compound of formula (I) containing a hydroxymethyl moiety may be converted into the corresponding compound containing a carboxy moiety by treatment with an oxidising agent such as tetrapropylammonium perruthenate.
  • a compound of formula (I) wherein R 1 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom may be prepared by reacting a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, with the appropriate compound of formula R'-H [e.g. 1- (pyridin-3-yl)piperazine or morpholine].
  • R'-H e.g. 1- (pyridin-3-yl)piperazine or morpholine.
  • the reaction is conveniently effected with the assistance of a transition metal catalyst, e.g.
  • amination ligand such as 2-dicyclohexylphosphino-2',4',6'-triisopropyl- biphenyl (XPhos) or 2,2'-bis(diphenylphosphino)-l, -binaphthalene (BINAP)
  • a base e.g. an inorganic base such as sodium tert-butoxide.
  • reaction may be effected using palladium diacetate, in the presence of a reagent such as [2',6'-bis(propan-2- yloxy)biphenyl-2-yl](dicyclohexyl)phosphane and a base, e.g. an inorganic base such as cesium carbonate.
  • a reagent such as [2',6'-bis(propan-2- yloxy)biphenyl-2-yl](dicyclohexyl)phosphane
  • a base e.g. an inorganic base such as cesium carbonate.
  • a compound of formula (I) containing an oxo moiety can be converted into the corresponding compound containing an ethoxycarbonylmethylidene moiety by treatment with triethyl phosphonoacetate in the presence of a base such as sodium hydride.
  • a compounds of formula (IIB), (UN), or (IIP) wherein R 9 represents ethenyl may be prepared by reacting a compound of (IIB), (IIN), or (IIP) wherein R 9 represents halogen, e.g. chloro, with potassium vinyl trifluoroborate.
  • the reaction is typically effected in the presence of a transition metal catalyst, e.g. [ ⁇ , - bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, e.g. an organic base such as triethylamine.
  • a compound of formula (IIB), (IIN), or (IIP) wherein R 9 represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R 9 represents an optionally substituted C 4 _ 7 cycloalkenyl moiety by treatment with the appropriately substituted cycloalkenyl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol.
  • the reaction is typically effected in the - -
  • a transition metal catalyst e.g. bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron-dichloropalladium-dichloromethane complex
  • a base e.g. an inorganic base such as potassium carbonate.
  • a compound of formula (IIB), (IIN), or (IIP) wherein R 9 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (IIB), (IIN), or (IIP) wherein R 9 represents halogen, e.g. chloro, with the appropriate compound of formula R 9 -H [e.g.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned.
  • protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit the binding of a fluorescence conjugate to TNFa when tested in the fluorescence polarisation assay described below. Moreover, certain compounds in accordance with this invention potently inhibit TNFa-induced NF- ⁇ activation in the reporter gene assay described below. - -
  • Compound (A) can be prepared by the procedure described in Example 499 of WO 2013/186229 (published 19 December 2013); or by a procedure analogous thereto.
  • TNFa and the fluorescence conjugate were 10 nM and 10 nM respectively in a total assay volume of 25 ⁇ . Plates were read on a plate reader capable of detecting fluorescence polarisation (e.g. an Analyst HT plate reader; or an Envision plate reader). An IC 50 value was calculated using XLfitTM (4 parameter logistic model) in ActivityBase.
  • HEK-293 cells Stimulation of HEK-293 cells by TNFa leads to activation of the NF- ⁇ pathway.
  • the reporter cell line used to determine TNFa activity was purchased from InvivoGen.
  • HEK-BlueTM CD40L is a stable HEK-293 transfected cell line expressing SEAP (secreted embryonic alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a dose- dependent manner by TNFa, with an EC50 of 0.5 ng/niL for human TNFa.
  • THF Tetrahydrofuran AcOH: Acetic acid r.t.: Room temperature RT: retention time br.: Broad M: Mass
  • DIPEA N,N-di-z50-propylethylamine
  • DIAD Diisopropyl (E)-l,2-diazenedicarboxylate
  • BAST bis(2-methoxyethyl)aminosulfur trifluoride
  • the methanolic ammonia solution is made by mixing 100 mL of an aqueous, solution of 37% w/w of NH 4 OH in 900 mL of MeOH.
  • Method 2 Preparative HPLC for all compounds that required it was performed at pH 2.5 using a Luna CI 8, 21.2 mm, 5 mm column.
  • Mobile phase A 99.92 % water and 0.08 % formic acid.
  • Mobile phase B 99.92 % MeCN and 0.08 % formic acid.
  • Step 2 preparation of ethyl 6-bromo-7-fluoro-imidazofl,2-aJpyridine-2-carboxylate
  • Step 4 preparation of ethyl 6-bromo-7 -fluoro-3- [hydroxy (phenyl)methylj 'imidazo [ 1 ,2- aJpyridine-2-carboxylate
  • Step 5 preparation of ethyl 6-bromo-3-[chloro(phenyl)methyl]-7-fluoro-imidazo[l,2- aJpyridine-2-carboxylate
  • Step 6 preparation of diethyl 2-f ( 6-bromo-2-ethoxycarbonyl- 7-fluoro-imidazof 1,2- a]pyridin-3-yl)-phenyl-methyl]propanedioate

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Abstract

La présente invention concerne une série de dérivés d'imidazole tricyclique condensé, en particulier des dérivés de dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridine, et leurs analogues, des modulateurs puissants de l'activité du TNF-alpha humain, qui sont donc utiles dans le traitement et/ou la prévention de diverses maladies humaines, notamment les troubles auto-immuns et inflammatoires, les troubles neurologiques et neurodégénératifs, les troubles nociceptifs et de la douleur, les troubles cardiovasculaires, les troubles métaboliques, les troubles oculaires et les troubles oncoloqigues.
PCT/EP2014/076884 2013-12-09 2014-12-08 Dérivés d'imidazole tricyclique condensé comme modulateurs de l'activité du tnf WO2015086526A1 (fr)

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BR112016012990A BR112016012990A2 (pt) 2013-12-09 2014-12-08 Derivados de imidazol tricíclicos fundidos como moduladores de atividade de tnf
CA2931758A CA2931758C (fr) 2013-12-09 2014-12-08 Derives d'imidazole tricyclique condense comme modulateurs de l'activite du tnf
JP2016537474A JP6445560B2 (ja) 2013-12-09 2014-12-08 Ｔｎｆ活性のモジュレーターとしての縮合三環式イミダゾール誘導体
CN201480067053.3A CN105814049B (zh) 2013-12-09 2014-12-08 作为tnf活性调节剂的稠合三环咪唑衍生物
ES14808658T ES2755335T3 (es) 2013-12-09 2014-12-08 Derivados de imidazoles tricíclicos fusionados como moduladores de la actividad del TNF
RU2016126974A RU2679914C9 (ru) 2013-12-09 2014-12-08 Конденсированные трициклические производные имидазола в качестве модуляторов активности tnf
US15/101,767 US10087179B2 (en) 2013-12-09 2014-12-08 Fused tricyclic imidazole derivatives as modulators of TNF activity
EP14808658.0A EP3080113B1 (fr) 2013-12-09 2014-12-08 Dérivés d'imidazole fusionnes tricycliques utilisables en tant que modulateurs de l'activité tnf

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WO2016133838A1 (fr) 2015-02-20 2016-08-25 Rigel Pharmaceuticals, Inc. Inhibiteurs du gdf 8
US9856253B2 (en) 2015-04-17 2018-01-02 Abbvie, Inc. Tricyclic modulators of TNF signaling
US10266532B2 (en) 2015-04-17 2019-04-23 Abbvie Inc. Tricyclic modulators of TNF signaling
WO2016168633A1 (fr) 2015-04-17 2016-10-20 Abbvie Inc. Indazolones utilisées en tant que modulateurs de la signalisation du tnf
US10273238B2 (en) 2015-04-17 2019-04-30 Abbvie Inc. Indazolones as modulators of TNF signaling
WO2016168641A1 (fr) * 2015-04-17 2016-10-20 Abbvie Inc. Modulateurs tricycliques de la signalisation du tnf
US9879016B2 (en) 2015-04-17 2018-01-30 Abbvie Inc. Indazolones as modulators of TNF signaling
US10160748B2 (en) 2015-04-17 2018-12-25 Abbvie Inc. Indazolones as modulators of tnf signaling
EP3288931B1 (fr) 2015-04-28 2019-11-06 Chongqing Fochon Pharmaceutical Co., Ltd. Inhibiteurs de certaines protéines kinases
US10472362B2 (en) 2015-06-08 2019-11-12 Ucb Biopharma Sprl Fused tricyclic imidazo pyrazines as modulators of TNF activity
WO2016198398A1 (fr) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Imidazopyrazines tricycliques condensées à titre de modulateurs de l'activité du tnf
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CA2931758C (fr) 2022-10-25
US20160376268A1 (en) 2016-12-29
RU2679914C9 (ru) 2019-03-19
EP3080113A1 (fr) 2016-10-19
US10087179B2 (en) 2018-10-02
BR112016012990A2 (pt) 2017-08-08
RU2016126974A (ru) 2018-01-23
GB201321729D0 (en) 2014-01-22

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